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Angiotensin-Converting Enzyme Inhibitors or -Blockers in

Heart Failure
Does It Matter Who Goes First?
James C. Fang, MD

ngiotensin-converting enzyme (ACE) inhibitors and the first drug rather than the second drug started is more likely to
-blockers are potent therapies in heart failure. They be titrated to target doses used in the clinical trials. Therefore, the
lower total mortality and heart failure hospitalizations benefits of effective -blockade, which are dose related,14 may
by 25% to 40% across all ages, functional capacities, degrees of be attenuated. Being first no longer appears to be sufficient
left ventricular dysfunction, and causes.1,2 But does it matter rationale to justify the optimal sequence to initiate these agents.
which intervention is given first? There are 2 primary reasons After all, digoxin, once favored as a first-line agent (and
why clinicians initiate heart failure therapy with ACE inhibitors certainly our oldest agent in heart failure), is now considered
for patients with systolic dysfunction: (1) ACE inhibitors were second-line therapy with a Class II recommendation in the 2005
the first agents to demonstrate a mortality benefit in heart failure American College of Cardiology/American Heart Association
and therefore have since served as background therapy for all heart failure guidelines.
heart failure trials, and (2) heart failure is a hemodynamic as well Two previous trials have suggested that a -blockerfirst
as a neurohormonal condition that acutely improves with vaso- strategy is safe and potentially beneficial. In the multicenter
dilation.3 In acutely decompensated patients, initial hemodynam- Carvedilol and ACE-Inhibitor Remodelling Mild Heart Failure
ic stabilization through vasodilation improves the neurohor- Evaluation (CARMEN) trial,12 572 patients with mild heart
monal profile, including a reduction in norepinephrine levels.4 failure and clinically stable for 2 weeks were randomly assigned
This stabilization may allow the subsequent introduction of in a blinded fashion to carvedilol 25 mg twice daily, enalapril 10
-blockers, which are acutely associated with a decline in mg twice daily, or the combination (with titration first of
ventricular function.5,6 carvedilol) for 18 months. Combination therapy led to a greater
Article p 2426 improvement in end systolic volume followed by carvedilol and
enalapril monotherapy. Most importantly, safety, mortality, hos-
However, when a patient has compensated heart failure, pitalizations, and withdrawal rates were comparable in all 3 trial
would a -blocker first be tolerated, safe, and even better? There
arms. In a smaller single-center nonblinded study,15 78 NYHA
are putative reasons why -blockers first may lead to greater
class II/III patients with newly diagnosed idiopathic dilated
survival and improved quality of life. The adrenergic system is
cardiomyopathy were randomized to 6 months of either carve-
activated earlier than the renin-angiotensin system (RAS)7 and is
dilol or perindopril first followed by titration of the second agent
an important stimulus for RAS activation. Norepinephrine is a
with functional class and ejection fraction as primary end points.
potent predictor of mortality.8 Enhanced sympathetic renal
The carvedilol-first group reached a greater total carvedilol dose
activity may contribute to sodium and water avidity.9 Evidence
(4317 mg versus 3318 mg, P0.03), had greater improve-
suggests that there is less escape and greater suppression of
ment in symptoms, had a greater ejection fraction (1516%
angiotensin II by ACE inhibitors when the adrenergic system is
versus 613%, P0.05), and experienced greater lowering of
also blocked.10 Cardiorenal complications of heart failure may
plasma N-terminal pro-brain natriuretic protein (166142
be avoided because rises in serum creatinine with ACE inhibi-
tors may be decreased by pretreatment with a -blocker.11 pg/mL versus 51384 pg/mL, P0.02).
-Blockers may have a greater impact on ventricular remodeling It is against this background that the CIBIS III investigators16
than ACE inhibitors.12 In contrast to ACE inhibitors,2 -blockers are to be congratulated for undertaking a trial with a large sample
also appear to have a greater impact on the lowering of sudden size that addresses both the safety and efficacy of a -blocker
death risk, which accounts for one half to two thirds of total first strategy in heart failure. The investigators randomized 1010
mortality in moderate heart failure.13 Finally, in clinical practice 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
The opinions expressed in this article are not necessarily those of the daily) for 6 months followed by uptitration of the second drug
editors or of the American Heart Association. for 6 to 24 months. The study randomization was not blinded,
From the Cardiovascular Division, Brigham and Womens Hospital,
Boston, Mass. but the end point and safety committees were blinded. The
Correspondence to James C. Fang, MD, Cardiovascular Division, investigators chose a conservative strategy of a noninferiority
Brigham and Womens Hospital, 75 Francis St, Boston, MA 02115. trial using a primary end point that combined all-cause mortality
(Circulation. 2005;112:2380-2382.)
and all-cause hospitalization. In the intention-to-treat sample,
2005 American Heart Association, Inc. there were 178 patients (35.2%) with a primary end point in the
Circulation is available at bisoprolol-first group compared with 186 (36.8%) in the
DOI: 10.1161/CIRCULATIONAHA.105.586545 enalapril-first group. Although the prespecified criteria for non-
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Fang ACE Inhibitors or -Blockers in Heart Failure 2381

inferiority was met with the intention-to-treat analysis (absolute priate because most patients 70 years old and with heart
difference 1.6%, 95% CI 7.6 to 4.4%, HR 0.94; 95% CI 0.77 failure will have a creatinine clearance 50 mL/min.
to 1.16), it did not quite meet the requirements of the per-protocol As anticipated, the first drug titrated resulted in a greater
analysis (the most rigorous analysis to use in noninferiority trials), proportion of patients taking the target dose of that drug
although it was close (absolute difference 0.7%, 95%CI 6.6 to during the combined therapy phase. For example, 64.8% of
5.1%, HR 0.97; 95% CI 0.78 to 1.21). There were 65 all-cause the bisoprolol-first group was taking 10 mg/day at the end of
deaths and 151 all-cause hospitalizations in the bisoprolol-first the study compared with 53.8% of the enalapril-first group,
group versus 73 deaths and 157 hospitalizations in the enalapril-first which may explain the survival difference seen; however, the
group; neither end point reached statistical significance. lack of blinding and open label design may have had a
Several issues are worthy of note. By design, the patients significant impact on these final doses. In contrast, only
studied were 1 decade older than those studied in most heart 42.5% of patients in CIBIS II reached this goal dose when
failure trials (ie, 72 versus 62 years old). In part, this older age both active and placebo arms were blinded.17
led the investigators to use a 6-month period of monotherapy The study has other limitations and these were acknowledged
because rapid additions of multiple therapies are often not by the authors. It did not meet the strictest criteria for noninfe-
tolerated in elderly patients. Although some practitioners may riority because the per-protocol analysis boundaries were not
find withholding ACE inhibitors in symptomatic but ambulatory met. (In a per-protocol analysis, only patients who strictly
patients troublesome, participating institutional review boards followed the protocol to the end of the study are included in the
did not find fault with this practice. More important, patients analysis.) As outlined by the investigators, however, the statis-
were excluded if they received RAS antagonists and/or tical power of such an analysis was reduced because the number
-blockers for 7 days in the 3 months before randomization, so of patients diminished rapidly with time and brings to light that
the findings are not confounded by pretreatment effects. Clinical there were a significant number of protocol violations and
stability for 7 days was also required before enrollment, which withdrawals (thus, the need for an intention-to-treat analysis in
would exclude many patients either hospitalized or recently most prospective randomized clinical trials).
hospitalized for heart failure. Titration of bisoprolol was also The study was not blinded, although the analyses of the end
cautious and slower than the protocol used in CIBIS II (respect- points were. The open study design was specifically chosen by
ing the older age of the study population and the lack of the investigators to allow separate titration of the drugs during
concomitant vasodilator therapy). This strategy was appropriate the follow-up combined-drug period because of a concern that
in that bisoprolol is a -1 selective agent without ancillary side effects could not be adequately addressed if blinding were
vasodilator properties that could limit its tolerability in the present. The lack of blinding could have lowered the threshold to
absence of a vasodilator during monotherapy titration. hospitalize for heart failure but not for other reasons in the
Despite the use of this titration protocol, there was some cause bisoprolol-first group (as was seen) and could have had an
for concern. The bisoprolol-first strategy was associated with a impact on the small difference in the numbers of deaths between
nonsignificant trend toward worsening of heart failure requiring groups. Although the authors address this problem, noting that
hospitalization or occurring in the hospital (63 versus 51, HR blinding of the end points committee limits bias,18 such blinding
1.25, 95% CI 0.87 to 1.81, P0.23) and may be a consequence does not eliminate bias.
of using a -1 selective agent without concomitant vasodilator Although there were trends toward fewer hospitalizations and
properties. This issue may have also resulted in a greater number fewer deaths in the bisoprolol-first group, the absolute differ-
of serious adverse events reported during the monotherapy ences were small and not conclusive (8 deaths, 6 hospitaliza-
phases of the bisoprolol-first arm as compared with the tions). Small absolute differences have been seen before in
enalapril-first arm (192 versus 163). Particular patients may be clinical trials but not confirmed in subsequent adequately pow-
especially prone to this issue because the percentage of patients ered studies (ie, remember the supposed mortality benefit of
reporting these events were similar between the 2 groups (22.4% losartan over captopril in ELITE I but not confirmed in ELITE
versus 22.1%), suggesting that more than one event occurred in II). Although the target doses used in the trial were the targets
the same patient. Despite this issue, there was little need in either used in the clinical trials of these drugs, many practice environ-
group to introduce the second agent early during monotherapy ments do not have the capacity to get patients to such doses over
for clinical reasons (bisoprolol-first 7.7% versus enalapril-first the course of weeks. It is not clear what the results would have
7.3%, P0.81). Furthermore, few patients in either arm discon- shown if the monotherapy duration were shorter than 6 months
tinued either drug during the monotherapy or combined-drug because many clinicians would be uncomfortable withholding
phases. During the entire trial, 60 bisoprolol-first patients and 59 ACE inhibitors for such a long period of time, despite the
enalapril-first patients withdrew formally from the trial. apparent safety of the practice in the trial. Most important, the
Patients with significant renal impairment (Cr 220 patients studied were ambulatory, compensated, and only mild
mol/L or 2.5 mg/dL) were also excluded, which is a to moderately symptomatic and therefore least prone to serious
common problem in older adults with heart failure. Further- hemodynamic collapse from the negative inotropic effects of
more, follow-up renal function was not reported but would be -blockers in the absence of background vasodilator therapy
of great interest considering the cardiorenal limitations in the with an ACE inhibitor.
treatment of elderly patients with heart failure. There did not What, then, should we take away from the CIBIS III trial?
appear to be a difference in outcome when renal function was We can feel safe that in mild to moderately symptomatic
stratified between a baseline creatinine clearance of 60 and elderly patients with heart failure who are ambulatory,
80 mL/min, but these ranges may not be the most appro- clinically compensated, and appropriately supervised, the use
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2382 Circulation October 18, 2005

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converting enzyme inhibitors on mortality and morbidity in patients with beta-antagonists angiotensin-converting enzyme inhibitors

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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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