Relationship of dose of background angiotensin-converting enzyme inhibitor to the benefits of candesartan in the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM)-Added trial

Abstract

Whether an angiotensin receptor blocker is of benefit when added to a full dose of angiotensin-converting enzyme (ACE) inhibitor in heart failure (HF) is uncertain.
The effect of candesartan, compared with placebo, in 2548 patients randomized in the CHARM-Added trial was analyzed according to (i) ACE inhibitor dose at baseline, (ii) ACE inhibitor dose during follow-up, and (iii) combination treatment with ACE inhibitor and beta-blocker at baseline. The main outcome was the composite of cardiovascular death or HF hospitalization.
The benefit of candesartan was not modified by the dose of ACE inhibitor. In all patients (n = 2548), the candesartan/placebo hazard ratio (HR) for the primary outcome was 0.85 (95% CI 0.75-0.96). In patients taking a guideline recommended dose of ACE inhibitor at baseline (n = 1291), this HR was 0.79 (95% CI 0.67-0.95; interaction P value .26). In patients taking a Food and Drug Administration-designated maximum dose of ACE inhibitor (n = 529), this HR was 0.75 (95% CI 0.57-0.98; interaction P value .29). The benefit of candesartan was preserved in patients taking beta-blockers in addition to a higher dose of ACE inhibitor and in patients maintaining a high dose of ACE inhibitor throughout follow-up.
These clinical findings support the pharmacologic evidence that ACE inhibitors and angiotensin receptor blockers have distinct mechanisms of action and show that their combined use improves outcomes in patients with HF more than an evidence-based dose of ACE inhibitor alone.

Full text

Congestive Heart Failure
Relationship of dose of background
angiotensin-converting enzyme inhibitor to the
benefits of candesartan in the Candesartan in Heart
failure: Assessment of Reduction in Mortality and
morbidity (CHARM)–Added trial
John J.V. McMurray, MB, MD,
a
James B. Young, MD,
b
Mark E. Dunlap, MD,
c
Christopher B. Granger, MD,
d
James Hainer, MD,
e
Eric L. Michelson, MD,
e
Steven Earle, PhD,
e
Bertil Olofsson, PhD,
f
Jan O
¨stergren, MD,
g
Salim Yusuf, MD, DPhil,
h
Karl Swedberg, MD, PhD,
i
and Marc A. Pfeffer, MD, PhD,
j
on behalf of the CHARM
Investigators Glasgow, Scotland; Cleveland, OH; Durham, NC; Wilmington, DE; Mo
¨lndal, Stockholm, and Go
¨teborg,
Sweden; Hamilton, Ontario, Canada; and Boston, MA
Background Whether an angiotensin receptor blocker is of benefit when added to a full dose of angiotensin-
converting enzyme (ACE) inhibitor in heart failure (HF) is uncertain.
Methods The effect of candesartan, compared with placebo, in 2548 patients randomized in the CHARM-Added trial
was analyzed according to (i) ACE inhibitor dose at baseline, (ii) ACE inhibitor dose during follow-up, and (iii)
combination treatment with ACE inhibitor and h-blocker at baseline. The main outcome was the composite of
cardiovascular death or HF hospitalization.
Results The benefit of candesartan was not modified by the dose of ACE inhibitor. In all patients (n = 2548), the
candesartan/placebo hazard ratio (HR) for the primary outcome was 0.85 (95% CI 0.75-0.96). In patients taking a guideline
recommended dose of ACE inhibitor at baseline (n = 1291), this HR was 0.79 (95% CI 0.67-0.95; interaction Pvalue .26). In
patients taking a Food and Drug Administration–designated maximum dose of ACE inhibitor (n = 529), this HR was 0.75 (95%
CI 0.57-0.98; interaction Pvalue .29). The benefit of candesartan was preserved in patients taking h-blockers in addition to a
higher dose of ACE inhibitor and in patients maintaining a high dose of ACE inhibitor throughout follow-up.
Conclusions These clinical findings support the pharmacologic evidence that ACE inhibitors and angiotensin receptor
blockers have distinct mechanisms of action and show that their combined use improves outcomes in patients with HF more
than an evidence-based dose of ACE inhibitor alone. (Am Heart J 2006;151:985291.)
The theoretical reasons for combining an angioten-
sin-converting enzyme (ACE) inhibitor and angiotensin
II type 1 receptor blocker (ARB) in heart failure (HF)
are well known.
1
However, for this strategy to be
valuable, clinically, it must offer benefits incremental
to those obtained with an optimal dose of an ACE
inhibitor. We present evidence that this is so, based
upon analyses of the CHARM-Added trial, which were
carried out during the approval process for candesar-
tan as a treatment of heart failure by the US Food and
Drug Administration (FDA).
Methods
Patients and procedures
The inclusion criteria for CHARM-Added were New York
Heart Association (NYHA) functional class II to IV, left
ventricular ejection fraction V40%, and a constant dose of ACE
From the
a
Department of Cardiology, Western Infirmary, Glasgow, Scotland,
b
Medicine,
Cleveland Clinic Foundation, Cleveland, OH,
c
Case Western Reserve University
and VA Medical Center, Cleveland, OH,
d
Duke University Medical Center, Durham,
NC,
e
AstraZeneca LP, Wilmington, DE,
f
AstraZeneca, R&D Mo
¨lndal, Sweden,
g
Depart-
ment of Medicine, Karolinska University Hospital Solna, Stockholm, Sweden,
h
HGM-
McMaster Clinic, Hamilton, Ontario, Canada,
i
Department of Medicine, Sahlgrenska
University Hospital/O
¨stra, Go
¨teborg, Sweden, and
j
Brigham and Women’s Hospital,
Boston, MA.
The CHARM program was funded by AstraZeneca, Wilmington, DE, which was
responsible for data collection and analysis. Academic leadership was provided by the
executive committee who supervised the management of the study and was responsible
for the interpretation of the data, preparation, review, and approval of the manuscript.
Authors who are employees of AstraZeneca are identified as such. All other authors have
received research grants, consultancy fees, and/or speaker fees from AstraZeneca.
Guest editor of this manuscript is Harvey D. White, DSc.
Submitted December 30, 2005; accepted February 14, 2006.
Reprint requests: John J.V. McMurray, MB, MD, Department of Cardiology, Western
Infirmary, G11 6NT Glasgow, UK.
E-mail: j.mcmurray@bio.gla.ac.uk
0002-8703/$ - see front matter
n2006 Mosby, Inc. All rights reserved.
doi:10.1016/j.ahj.2006.02.028

inhibitor for z30 days.
2
Investigators were given the target and
mean achieved doses ACE inhibitors shown to be of benefit in
randomized trials in HF and after myocardial infarction and
asked to individually optimize ACE inhibitor treatment ac-
cordingly, that is, to aim for an evidence-based target dose or,
failing that, the maximum tolerated dose of ACE inhibitor. The
study had ethical approval at all centers, and each patient gave
written informed consent.
Randomization, follow-up, and outcomes
Randomized treatment with candesartan or matching
placebo was usually started at a dose of 4 mg once daily, and
the dose was doubled at 2 weekly intervals, as tolerated,
according to a forced titration protocol with recommended
monitoring of blood pressure, serum creatinine, and potassi-
um. The target dose was 32 mg once daily from 6 to 8 weeks
onward (Figure 1).
The primary outcome in CHARM-Added was cardiovascu-
lar (CV) death or HF hospitalization. Other prespecified
outcomes included death or HF hospitalization and
all-cause mortality.
Subgroups
The 2 prespecified subgroup analyses divided patients
into those taking (1) the recommended dose or more, or
less than the recommended dose, of ACE inhibitor (based
on the European Society of Cardiology guidelines, Table I)
and (2) h-blocker or no h-blocker at baseline.
2
Post hoc subgroup analyses were carried out according to
1. Baseline treatment with an FDA-recommended maximum
dose of ACE inhibitor (communications, December 2004
and January 2005; Table II).
2. Maintenance of maximum dose of ACE inhibitor during
follow-up, until an outcome event or final visit.
3. Baseline treatment with maximum dose of ACE and
h-blocker.
Statistical methods
Hazard ratios (HRs) and corresponding 95% CIs for cande-
sartan versus placebo analyses within ACE inhibitor dose
Figure 1
Dosing and visit schedule in the CHARM-Added trial. Mean daily
dose (in milligrams) for the 5 most commonly used ACE inhibitors at
baseline (visit 1) and during the trial. ACEi , ACE inhibitor.
Table I. Daily dose of ACE inhibitors used in CHARM-Added and subgroup analyses by dose
ACE inhibitor
%on
Rx
Dose in
CHARM-Added
(mg/d)
zzzzzzzzzzz
__ Recommended
(CHARM prespecified),
*n = 1291
zzzzzzzzzzz
__ Maximum
(FDA),yyyyy n = 721
zzzzzzzzzzz
__ Maximum
(FDA revised),zzzz n = 529
Dose
(mg/d)
Patients
(%)
Dose
(mg/d)
Patients
(%)
Dose
(mg/d)
Patients
(%)
Enalapril 27 17 20 52 20 52 40 10
Lisinopril 19 18 20 52 40 15 20 52
Captopril 17 83 150 21 150 21 300 2
Ramipril 11 7 10 39 10 39 10 39
Trandolapril 6 2.5 2 90 4 27 4 27
Perindopril§64 483 161 161
Quinapril 525 2060 807 80 7
Fosinopril 520 2059 4020 4020
Benazepril§326 2062 805 80 5
Other§t1–
All 100 50.70 28.30 20.80
Rx, treatment.
4Based on the European Society of Cardiology guidelines [12].
yUS FDA communication, December 2004.
zFDA communication, January, 2005.
§Not approved by FDA for treatment of heart failure.
tCilazapril and moexipril.
American Heart Journal
May 2006
986 McMurray et al

groups were derived from Cox proportional hazard models
with only treatment in the model. The analyses were repeated
adjusting for 32 prospectively defined potential confounding
variables, as previously reported, with the exclusion of ACE
inhibitor use as a covariate.
2
Tests for heterogeneity across
subgroups were also conducted.
Results
The baseline characteristics of patients taking or not
taking a maximum dose of ACE inhibitor (FDA
recommendation, January 2005) are shown in Table II.
Overall, there was little difference between patients
in these 2 groups, though patients taking a higher dose
of ACE inhibitor were more likely to have a history
of hypertension.
Enalapril, lisinopril, captopril, ramipril, and trando-
lapril accounted for 80% of all ACE inhibitors used
(Table II). The mean daily doses were 16.8, 17.7,
82.2, 6.8, and 2.5 mg in the candesartan group and
17.2, 17.7, 82.7, 7.3, and 2.4 mg in the placebo
group. In the opinion of the site investigators, 96% of
the patients were on an optimum individualized dose
of ACE inhibitor. The dose was maintained during
follow-up (Figure 1). A recommended dose of ACE
inhibitor or more was used in 51% of the patients at
baseline and maintained in 47% of the candesartan
group and 50% of the placebo group at the 6
months’ visit (after completion of the study
drug titration).
Other treatments used at baseline (end of study)
included h-blocker 55% (64% candesartan and 68%
placebo) and spironolactone 17% (20% candesartan and
25% placebo).
Primary outcome in overall study and prespecified
subgroups
Four hundred eighty-three (37.9%) patients in the
candesartan and 538 (42.3%) in the placebo group
experienced CV death or HF hospitalization (HR 0.85;
95% CI 0.75-0.96, P= .011 unadjusted, P= .010
covariate adjusted) (Figure 2). Candesartan reduced this
risk in the 2 predefined subgroups with no evidence of
heterogeneity of treatment effect.
Post hoc subgroups
The results of the analyses, using the 2 higher ACE
inhibitor dose thresholds suggested by the FDA, are
shown in Figures 2 and 3. Baseline dose of ACE
inhibitor did not modify the effect of candesartan on
any clinical outcome.
Similarly, maintenance of a maximum ACE inhibitor
dose during study follow-up (Figure 4) or baseline
treatment with a combination of both a maximum dose
of ACE inhibitor and h-blocker did not modify the effect
of candesartan (Figure 5).
Components of primary outcome
The HR for CV death was 0.864 (95% CI 0.727-1.027)
in those not taking a maximum dose and 0.764 (95% CI
0.543-1.075) in those taking a maximum dose of ACE
inhibitor. The HR for heart failure hospitalization was
0.865 (95% CI 0.728-1.029) in those not taking a
maximum dose and 0.698 (95% CI 0.507-0.961) in
those taking a maximum dose. In other words, the
background ACE inhibitor dose did not modify the
effect of candesartan on either component of the
primary outcome.
Table II. Baseline characteristics of patients taking and not
taking a maximum dose of ACE inhibitor (as defined by the FDA
January 2005)
Not maximum
dose (n = 2019)
Maximum
dose (n = 529)
Age (y)
Mean (SD) 64 (11) 64 (11)
z65 (%) 50 49
Sex
Male (%) 78 81
Systolic BP (mm Hg)
Mean (SD) 125 (18) 126 (20)
b100 (%) 4.9 6.2
100 to b140 (%) 69.3 66.5
z140 (%) 25.8 27.2
Diastolic BP (mm Hg)
Mean (SD) 75 (11) 75 (11)
b70 (%) 22.7 27.6
70 to b90 (%) 64.0 58.6
z90 (%) 13.2 13.8
Etiology (%)
Ischemic 64 56
Idiopathic 25 30
Hypertensive 5.8 9.1
NYHA class (%)
II 25 22
III 72 76
IV 3.2 2.5
LVEF (%)
Mean (SD) 30 (10) 30 (10)
Medical history (%)
HF hospitalization 77 76
Myocardial infarction 57 50
Angina 53 52
Stroke 8.1 10.8
Hypertension 46 56
Diabetes mellitus 29 34
Atrial fibrillation 27 29
Concomitant medication (%)
Diuretic 90 92
Digitalis glycoside 58 60
h-Blocker 55 59
Spironolactone 17 16
Baseline creatinine (mg/dL)
z2.0 (%) 5.4 3.9
BP, blood pressure.
American Heart Journal
Volume 151, Number 5 McMurray et al 987

Tolerability
In CHARM-Added, the rates of study drug discontinu-
ation in the candesartan and placebo groups were
creatinine increase (7.8% vs 4.1%), hypotension (4.5% vs
3.1%), and hyperkalemia (3.4% vs 0.7%). These rates in
the subgroup taking a maximum dose of ACE inhibitor
(second definition) were 7.4% versus 8.1%, 4.5% versus
3.1%, and 4.1% versus 1.5%, respectively.
Figure 2
Primary outcome of CV death or HF hospitalization for patients in CHARM-Added at recommended or higher dose of ACE inhibitor or maximum
dose of ACE inhibitor as defined by the US FDA in the communication of December 2004 and as revised in January 2005. Also presented are the
results for CHARM-Alternative (no ACEi) and the pooled results for these 2 trials in patients with low LVEF. ACEi , ACE inhibitor.
Figure 3
Outcome analyses based on recommended or higher ACE inhibitor dose at baseline, and maximum or higher (as defined by FDA in January
2005) ACE inhibitor dose at baseline.
American Heart Journal
May 2006
988 McMurray et al

Figure 4
Outcome analyses in a subgroup of patients maintained at recommended or higher ACE inhibitor (ACEi) dose during the trial, and maximum or
higher (as defined by FDA in January 2005) ACE inhibitor dose during the CHARM-Added trial.
Figure 5
Outcome analyses in the subgroup of patients taking a h-blocker at baseline (n = 1413) and either recommended or higher ACE inhibitor dose at
baseline, or maximum or higher (as defined by FDA in January, 2005) ACE inhibitor dose at baseline.
American Heart Journal
Volume 151, Number 5 McMurray et al 989

Discussion
The CHARM investigators used evidence-based
doses of ACE inhibitors, and there was a clinical
benefit of adding candesartan irrespective of ACE
inhibitor dose.
The most studied ACE inhibitor in HF (and most
commonly used in CHARM-Added) is enalapril.
3-7
The
target and mean achieved daily doses in the 5 large
trials that used forced titration were CONSENSUS
(target 20 mg BID, mean achieved daily dose 18.4 mg),
SOLVD-Treatment (T) (10 mg BID, 16.6 mg), V-HeFT II
(10 mg BID, 15.0 mg), OVERTURE (10 mg BID,
17.7 mg), and CARMEN (10 mg BID, 16.8 mg, and
14.9 mg in the group receiving active treatment with
the h-blocker carvedilol).
3-7
In CHARM-Added, the
mean daily dose was 17.0 mg. The doses of ACE
inhibitor used in CHARM-Added exceed those in other
recent add-on trials in HF (eg, daily enalapril dose of
15 mg in RALES and 14 mg in MERIT-HF) and greatly
exceed those used in clinical practice (weighted mean
daily dose of enalapril from 13,764 patients in 7
community and hospital studies 13.8 mg).
8-10
The dose
of ACE inhibitor was maintained during follow-up in
the candesartan group in CHARM-Added. Despite all of
these, there was a benefit from adding candesartan.
Could the same benefit have been obtained by
increasing the dose of ACE inhibitor, above those
shown to be effective in prior trials? This hypothetical
question has 2 parts. First, would patients tolerate
higher doses? Other than the data from the large
randomized trials such as SOLVD-T in which 51% of
the patients could not be titrated up to 10 mg of
enalapril twice daily (despite an active run-in period),
there is very little other information on this subject.
4
The mean achieved daily dose of enalapril (18.4 mg)
in CONSENSUS where the target dose was 20 mg BID
was only slightly higher than in SOLVD-T (16.6 mg)
3
,
and only 22% of patients reached the target dose.
Some patients can tolerate larger doses, but how
representative these are of all patients with HF is
unknown. Of greater importance is the second part of
the question; that is, even if patients can be titrated
to higher than evidence-based doses of ACE inhibitors,
will this lead to greater clinical benefit? Only one trial
compared an evidence-based dose to a higher dose,
randomizing 248 patients with symptomatic HF and
left ventricular ejection fraction (LVEF) V35% to
enalapril 20 or 60 mg daily.
11
The mean doses
achieved were 17.9 and 42.5 mg daily, respectively
(72.5% and 32.5%, respectively, reached the target
dose by 3 months). After 12 months, there was no
difference in mortality or morbidity between the 2
treatment groups, although the number of events was
small. There was also no statistically significant or
clinically meaningful difference in blood pressure,
heart rate, left ventricular ejection fraction, or NYHA
functional class.
Overall, therefore, the effect of candesartan was
similar in patients taking no ACE inhibitor (CHARM-
Alternative), a moderate dose of ACE inhibitor (all
patients in CHARM-Added), or a high dose of ACE
inhibitor (maximum dose subgroup analysis of CHARM-
Added). These findings support the pharmacologic
evidence that ACE inhibitors and ARBs have distinct
mechanisms of action and that, clinically, these 2 classes
of drug can complement each other in a way that
improves outcomes in patients with HF. A more
stringent test of this hypothesis, however, would be a
prospective randomized comparison of the effect of
adding either additional ACE inhibitor or an ARB on
clinical outcomes in patients with HF.
In summary, candesartan is beneficial in patients with
HF receiving conventional treatment, including a
h-blocker, irrespective of background dose of ACE
inhibitor. Moreover, the addition of the ARB candesartan
improves outcomes beyond those achievable with even
an optimal or maximum dose of ACE inhibitor.
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