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International Journal of Cardiology 93 (2004) 105 – 111
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Review
Meta-analyses of mortality and morbidity effects of an angiotensin
receptor blocker in patients with chronic heart failure already
receiving an ACE inhibitor (alone or with a h-blocker)
Konstantinos Dimopoulos a,b,*, Tushar V. Salukhe a,b, Andrew J.S. Coats a,c,
Jamil Mayet a,d, Massimo Piepoli a,e, Darrel P. Francis a,d
b
a
National Heart and Lung Institute, London, UK
Heart Failure Unit, Royal Brompton Hospital, Sydney St., London SW3 6NP, UK
c
Sydney University Medical School, Sydney, Australia
d
St. Mary’s Hospital, London, UK
e
Ospedale Civile di Piacenza, Italy
Received 1 October 2003; accepted 9 October 2003
Abstract
Background: While treatment with either angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) is
clearly superior to placebo in the treatment of heart failure patients, controversy still surrounds the effects of ARBs in patients already
receiving an ACEi. Even more controversial is the wisdom of administering ARBs in patients already on an ACEi and h-blocker. Methods:
We present meta-analyses of the available randomised controlled trials to date (October 2003) of angiotensin II receptor antagonists versus
placebo in patients with symptomatic chronic heart failure in which both groups received ACEi. The two largest eligible trials were CHARMAdded and Val-HeFT. We examined two endpoints: mortality and a combined endpoint of mortality and morbidity. Results: In the first metaanalysis, covering all patients regardless of h-blocker use, we found a significant reduction in the combined endpoint (odds ratio [OR] = 0.89;
95% confidence interval [CI] 0.81 – 0.98), but no significant reduction in mortality itself (OR = 0.97; CI: 0.87 – 1.08). In the second metaanalysis, covering patients concomitantly on h-blockers, we found no significant effect on mortality (OR = 1.08; CI: 0.90 – 1.29) or on the
combined endpoint (OR = 0.94; CI: 0.82 – 1.10). In the third meta-analysis, covering patients not on concomitant h-blockers, there is clear
evidence of a reduction in the combined endpoint (OR = 0.83; CI: 0.73 – 0.94), but not on mortality (OR = 0.93; CI: 0.81 – 1.06). Conclusion:
There is now good evidence for the use of ARBs to prevent events in patients with heart failure on ACEi who are not suitable for h-blockers.
D 2004 Published by Elsevier Ireland Ltd.
Keywords: Meta-analysis; Heart failure; Angiotensin receptor II antagonists
1. Introduction
Controversy surrounds the use of angiotensin receptor
blockers (ARBs) in patients with chronic heart failure who
are already receiving angiotensin converting enzyme inhibitors (ACEi). Theoretically, ARBs can antagonise angiotensin II produced by enzymes other than ACE and therefore
could potentially further suppress the effects of overactivation of the renin – angiotensin– aldosterone system.
* Corresponding author. Heart Failure Unit, Royal Brompton Hospital,
Sydney St., London SW3 6NP, UK. Tel.: +44-780-051-0072; fax: +44-208429-2312.
E-mail address: [email protected] (K. Dimopoulos).
In particular, in patients already receiving both a hblocker and an ACEi, it is especially controversial
whether the effect of adding an ARB is harmful or
beneficial.
Data is now available from large randomised controlled
trials that should help to evaluate whether the theoretical
benefit of ARBs in patients already taking ACEi translates
into reduced clinical events. From two large studies (ValHeFT, CHARM), there are also data stratifying the
patients according to whether they were receiving hblockers.
Quantitative synthesis by meta-analysis is the most
reliable way of putting together results of large randomised
controlled trials. We performed a meta-analysis of trials of
ARBs versus placebo in patients receiving ACEi for chronic
0167-5273/$ - see front matter D 2004 Published by Elsevier Ireland Ltd.
doi:10.1016/j.ijcard.2003.10.001
IJCA-05331; No of Pages 7
2
Study
Population
ARBS
ACEi
Control
Primary
endpoint
Hamroff [3]
NYHA III – IV
losartan
placebo
peak VO2,
NYHA class
RESOLVD [4]
NYHA II – IV,
6 MWD < 500 m,
EF < 40%
candesartan
various
(enalapril, captopril,
fosinopril, lisinopril)
enalapril
placebo vs.
candesartan
vs. enalapril
Val-HeFT[5,27]
II – IV,
EF < 40%
LVEDD>2.9 cm/m2
valsartan
various
(enalapril, lisinopril,
quinazil, ramipril,
captopril)
placebo
CHARM-Added [6]
NYHA III – IV,
NYHA II plus
hospitalization
last 6 months
candesartan
various
(enalapril, lisinopril,
captopril, ramipril, etc.)
placebo
6-min walk test,
EF,
LV volumes,
neurohormones,
QOL, clinical
events
mortality/mortality
and morbidity
(hospitalization,
SCD with
resuscitation,
IV vasodilators or
inotropes >4 h)
mortality or
hospitalization
Overall
Total number
of patients
Patients in
ARB arm
Mean
follow-up
(months)
Mortality
(%)
6
Mortality
per year of
follow-up
(%)
33
16
6
12.1
441
332
47
7.4
1.9
4644
2326
23
19.5
10.1
2548
1276
41
25.4
7.4
7666
3950
31
21.6
8.6
ACEi=ACE inhibitor; ARBs=angiotensin receptor blocker; EF=ejection fraction; LV=left ventricle; LVEDD=left ventricular end diastolic diameter; NYHA=New York Heart Association; VO2=Oxygen
consumption; 6MWD=6-min walk distance; QOL=Quality of Life; SCD=sudden cardiac death.
K. Dimopoulos et al. / International Journal of Cardiology 93 (2004) 105–111
Table 1
Randomised controlled trials involving ARBs and ACEi therapy versus placebo plus ACEi, mean treatment duration >6 months, primary outcome mortality, or mortality – morbidity
K. Dimopoulos et al. / International Journal of Cardiology 93 (2004) 105–111
3
2.3. Statistical analysis
heart failure. We also performed separate meta-analyses of
subgroups of patients according to whether they were
receiving concomitant beta-blockade.
For each of the three meta-analyses (all patients;
patients on h-blockers; patients not on h-blockers), we
calculated the effects of added ARB on (i) mortality and
(ii) a combined endpoint of mortality and morbidity. The
odds ratio (OR) method was used to combine the individual study effect sizes into a single overall effect size,
expressed as odds ratio and 95% confidence interval
(CI).[1] A fixed effect model was used initially, but if
there was evidence of heterogeneity by the Cochran Q
method [2] ( p < 0.05 by v2), we moved on to the random
effects model.
2. Methods
We assessed the available randomised controlled trials
to date (October 2003) of ARBs versus placebo in
patients with symptomatic chronic heart failure in which
both groups received ACEi. Our primary endpoint was
mortality. Secondarily, we evaluated the effect on the
combined endpoint of mortality and morbidity. Since the
trials used different definitions of this combined endpoint,
we decided that the only unbiased solution was to use the
prespecified combined endpoint within the individual
trials.
3. Results
3.1. Trial characteristics
2.1. Presence of concomitant b-blocker therapy
A total of four randomised controlled studies met
the entrance criteria, with a total of 7666 patients
(Table 1). All were double-blind, randomised placebocontrolled studies in which comparison between combined ARBs plus ACEi therapy was compared to ACEi
alone.
Three types of ARBs were being tested in these
studies: losartan, valsartan and candesartan. As for the
ACEi used as background therapy, in only one trial was
the ACEi constant (enalapril in the RESOLVD trial).
Patients in the remaining studies were on treatment with
various open-label ACEi. In one study (RESOLVD), we
considered the ACEi alone and ACEi plus ARB arms
only.
All-cause mortality was reported in all studies. Combined
endpoint expressed as mortality or morbidity was reported
in all but one study [3].
Mortality and morbidity characteristics of the subgroups with and without concomitant h-blockers were
reported in two studies (Val-HeFT and CHARMAdded). In the RESOLVD and Val-HeFT studies, not
all patients were treated with an ACEi, and only the
subgroups that were are included in this meta-analysis
(Table 2).
We performed one analysis (a) pooling all patients
irrespective of whether they were on concomitant h-blockade. Where studies reported separate results for patients
with and without concomitant h-blockade, we were able to
include those studies in additional meta-analyses of (b)
patients on concomitant ACEi and h-blocker and (c)
patients on concomitant ACEi without h-blocker.
2.2. Study selection
A systematic MEDLINE search was performed using key
search words: angiotensin receptor antagonist (or blocker),
heart failure, angiotensin converting enzyme (or ACE)
inhibitor and randomised controlled trial. We specifically
identified (i) double-blinded randomised controlled studies
of combined ARB and ACEi therapy versus ACEi therapy
alone in patients with symptomatic heart failure (NYHA II –
IV); (ii) studies with mortality and morbidity as a primary
outcome; and (iii) with duration of follow-up of at least 6
months.
Data were extracted by two readers independently, and a
third reviewer was used in the eventuality of disagreement
between the two.
Table 2
Baseline demographic data and clinical characteristics
Study
Mean age
(years)
Male
(%)
NYHA
Class II/III/IV (mean)
Mean
LVEF (%)
Ischemic/idiopathic
etiology (%)
% on
digoxin
% on
diuretic
% on
h-blocker
Hamroff
RESOLVD
Val-HeFT
CHARM
-Added
Overall
61
63
63
64
49
86
80
79
NA
63:35:2 (2.3)
62:36:2 (2.3)
24:73:3 (2.7)
26
28
27
28
30:70
71:18
57:31
62:26
97
68
67
58
100
85
85.5
90
6
15
35
55
63.2
79.8
49.3:48.3:2.3 (2.5)
25.6
59.6:28.8
64.5
NYHA = New York Heart Association, LVEF = left ventricular ejection fraction, NA = not available.
87.0
40.5
4
K. Dimopoulos et al. / International Journal of Cardiology 93 (2004) 105–111
Fig. 1. Effect of ARBs on mortality and the combined endpoint mortality –
morbidity in patients with heart failure taking ACE inhibitors, regardless of
h-blocker therapy. The OR and 95% confidence interval are shown for each
study and overall.
3.2. ARB versus no ARB in patients taking ACEi
(regardless of b-blocker therapy)
A total of 3950 patients were randomised to combined
ARB and ACEi therapy, whereas 3716 patients were randomised to ACEi plus placebo. Mean age was 63.2 years and
79.8% were men. Mean NYHA class was 2.5, and 59.6%
had heart failure of ischemic aetiology. Only 40.5% were on
h-blocker therapy.
All-cause mortality was not significantly affected by
ARB treatment (OR = 0.97; 95% CI: 0.87 –1.08) (Fig. 1).
The combined endpoint showed subtle evidence of benefit
from ARB treatment in the fixed effects model (OR = 0.89;
95% CI: 0.81 –0.98). There was no evidence of heterogeneity with either endpoint.
Fig. 3. Effect of ARBs on mortality and the combined endpoint of
mortality – morbidity in patients with heart failure taking ACEi but not hblockers. The odds ratio and 95% confidence interval are shown for each
study and overall.
3.3. ARB versus no ARB in patients taking ACEi
and b-blocker
A total of 3163 patients were on h-blocker therapy, of
which 1569 were randomised to ARB and 1594 to no ARB
in the Val-HeFT and CHARM-Added trials.
Mortality in the two groups was 23.3% and 24.1%,
respectively. No significant difference in mortality was seen
between the two groups by the fixed effects model
(OR = 1.08; 95% CI: 0.90 –1.29, Fig. 2). Because of evidence of heterogeneity [v2 = 6.8, p < 0.05], the random
effects model was also calculated, which confirmed no
significant treatment effect (OR = 1.12; 95% CI: 0.69– 1.81).
Combined mortality and morbidity was also not significantly different (OR = 0.94; 95% CI: 0.80– 1.10) by the
fixed effects model. Because of evidence of heterogeneity
[v2 = 9.2, p < 0.05], the random effects model was also
calculated, and this confirmed no significant treatment effect
(OR = 0.95; 95% CI: 0.59– 1.54 ).
3.4. ARB versus no ARB in patients taking ACEi but
not b-blocker
A total of 4029 patients were in the non-h-blockers
subgroups of the Val-HeFT and CHARM-Added trials.
Mortality was not significantly different between the ARB
and non-ARB arms (OR = 0.93; 95% CI: 0.81 – 1.06, fixed
model; no evidence of heterogeneity). The combined endpoint of mortality and morbidity was significantly reduced
in the ARB arm (OR = 0.83; 95% CI: 0.73– 0.94, fixed
model; no evidence of heterogeneity) (Fig. 3).
Fig. 2. Effect of ARBs on mortality and the combined endpoint of
mortality – morbidity in patients with heart failure taking ACE inhibitors
and h-blockers. The odds ratio and 95% confidence interval are shown for
each study and overall.
4. Discussion
In these meta-analyses, we have found that ARBs have a
beneficial effect in patients who are taking ACEi, as long as
K. Dimopoulos et al. / International Journal of Cardiology 93 (2004) 105–111
they are not taking h-blockers. The reduction in the combined endpoint is not accompanied by reduction in mortality, suggesting that the benefit might be largely through
reduction in hospitalization.
The deleterious effects of neurohormonal activation in
the context of chronic heart failure have been the dominant
treatment targets of recent decades. High levels of catecholamines, renin and aldosterone have negative effects on the
cardiovascular system producing progressive impairment of
left ventricular structure and function as well as vascular
damage.[5,7 – 11] ACEi are clearly beneficial for prognosis,
even though doubts remain on optimal dosage and interactions with other drugs.[12 13] However, ACEi alone, even
if at full recommended doses, does not provide complete
inhibition of the renin – angiotensin converting enzyme
system (RAS), thus permitting angiotensin to exert its
negative systemic effects. [14 – 17]. ARBs, on the other
hand, have been shown to be safe and have similar efficacy
to ACEi in heart failure. [18 –21] A combined approach
using both ACEi and ARBs could provide a more effective
blockade of the RAS than either drug alone. [22] Moreover,
the beneficial effects of ACEi and ARBs may go beyond
inhibition of the RAS [23 24]. ACEi increase kinin levels
since ACE is also a potent kininase. ARBs may enhance the
activation of ATII receptors by inducing circulating levels of
angiotensin, thus triggering kinin generation and nitric oxide
production. [23 24].
4.1. Studies of ARB on a background of ACEi
The first clinical trial to compare ACEi treatment to the
combination ACEi plus ARBs in patients with heart failure
was published by Hamroff et al. Even though the study was
underpowered for survival analysis, a clear beneficial effect
on the primary endpoints of exercise capacity and functional
class was seen after a mean observation time of 6 months,
suggesting an additive effect of ACEi and ARBs [3].
The RESOLVD pilot study showed a beneficial effect
of the combination strategy on blood pressure, left ventricular dimensions and neurohormonal factors (renin,
epinephrine, N-terminal pro-atrial natriuretic peptide). [4]
The ACEi plus ARB arm also showed the greatest increase
in renin and greatest decrease in aldosterone, suggesting a
more effective blockage of the RAS. No significant differences were seen in mortality and morbidity, leaving doubts
on the long-term survival benefits of the combination
therapy. It is nevertheless noteworthy that the ACEi arm
consisted of only 109 patients and a significantly lower
proportion of patients took h-blockers in the ARB arm
than in the non-ARB arm, possibly affecting survival
analysis in this study.
The Val-HeFT Study compared valsartan to placebo in
heart failure patients, the vast majority of which were on
ACEi. [5] Even though a large population of patients was
included and mean observation period was nearly 2 years,
a significant effect of the combination therapy was only
5
seen on morbidity expressed as hospitalization, whereas
mortality was similar in the two groups. An unexpected
increase in mortality emerged during post hoc analysis in
the subgroup of patients on triple therapy (ARB, ACEi and
h-blocker): 129 versus 97 deaths, HR 1.42, 95% CI: 1.09–
1.85. Doubts were raised on whether this was a true
harmful effect of excessive neurohormonal blockade by
the triple therapy or a manifestation of the random play of
chance.
The CHARM-Added Study was recently published,
comparing candesartan to placebo in a large population of
heart failure patients already on ACEi. It was large and had
a long mean observation period of more than 3 years and
was thus potentially capable of answering the questions that
Val-HeFT had raised. There was a significant decrease in the
primary endpoint of death or hospitalization for worsening
heart failure in the ARB plus ACEi arm, which had not been
seen in Val-HeFT. In mortality, however, there was no
significant difference. Subgroup analysis showed that the
addition of h-blockers to the combination ACEi-ARB as
well as administration of the maximum recommended doses
of ACEi were the two factors that conferred the maximum
benefit.
Paradoxically, therefore, the CHARM-Added results favoured triple therapy (ACEi-ARBS-h-blocker), while ValHeFT had suggested that such combination could be harmful. The present meta-analysis was largely dependent on
these two discordant studies since, as the largest two trials
ever on this question, they were responsible for the vast
majority of events.
4.2. Quantitative synthesis by meta-analysis
Across the trials as a whole, all-cause mortality is not
significantly affected by ARB. There is a borderline reduction in combined endpoint, which is significant by the fixed
effect model, but nonsignificant in the random effects
model, which is more appropriate in a meta-analysis with
this degree of heterogeneity. Our conclusion is therefore that
at present, there is not good endpoint-based evidence for
routine administration of ARB across all patients receiving
ACEi for heart failure.
Within the subgroup taking h-blockers, there is no
evidence of reduced mortality nor of reduce combined
endpoint. The apparent increase in mortality seen in ValHeFT is neutralised by the nonsignificant trend to reduce
mortality in CHARM-Added. In a mirror-image situation,
the reduced combine endpoint in CHARM-Added is neutralised by a nonsignificant trend to increased combined
endpoint in Val-HeFT. We conclude that there are no
grounds to recommend routine ARBs receiving both ACEi
and h-blockers.
Those patients not taking h-blockers, however, had clear
evidence of reduction, the combined endpoint of morbidity
and mortality when ARB was added to a background of
ACEi, although mortality itself was not significantly re-
6
K. Dimopoulos et al. / International Journal of Cardiology 93 (2004) 105–111
duced. We can therefore conclude that for patients not
taking h-blockers, adding an ARB reduces the clinical
events, largely (or entirely) by reducing hospital admissions/morbidity. Our meta-analysis thus furthers the previous meta-analysis by Jong et al. [25], since data newly
available (CHARM-Added) demonstrate a significant benefit of double treatment on the combined endpoint of
mortality and morbidity.
4.3. Possible mechanisms
Why does adding ARBs to ACEi only seem to help those
patients not on h-blockers? It could be a consequence of an
interaction between AT1 receptors and h-adrenergic receptors.[26] It has been shown that selective AT1 receptor
blockade inhibits downstream signalling of h-adrenergic
receptors, thus producing a h-blocker effect. It may be that
the benefit derives mainly from the h-blocking properties of
ARBs.
Why was there such a contrast between the results of ValHeFT and CHARM-Added in the subset of patients on hblockers? Differences in baseline characteristics of these
two large trials that could explain the difference. First, being
a more recent study, CHARM-Added had a significantly
higher proportion of patients on h-blockers than Val-HeFT
(Table 1). Second, the vast majority of patients in the ValHeFT were in NYHA class II, whereas the majority of
patients in CHARM-Added were in class III. The sicker
CHARM-Added patients may have had more neurohormonal activation and therefore more opportunity to benefit from
a more complete neurohormonal blockade provided by the
triple therapy. Our meta-analysis combines the two populations, producing a more homogeneous distribution between
the two main functional classes (II and III, 49.3% and
48.3%, respectively) of chronic heart failure. Perhaps triple
therapy may in the future be proved beneficial in the more
impaired patients. More studies would be required to clarify
this question.
4.4. Study limitations
The key limitation was the small number of studies
available on combined ACEi and ARBs treatment. Moreover, there was evidence of heterogeneity in some of the
analyses. Nevertheless, the overall population was large
enough to permit analysis and identify certain key results,
and recalculations (as presented in Results) using a randomeffects model in those analyses showing heterogeneity did
not affect the conclusions.
Secondly, three different ARBs were used in the studies
included in this meta-analysis, and only one used a uniform
ACEi, whereas the rest used several ACEi, as long as
treatment was optimal. We are therefore indirectly considering ACEi to have a class effect. While this viewpoint
would be widely held by clinicians to be valid, there is no
proof of a uniform class effect.
Thirdly, the proportion of patients on h-blockers varied
depending on the age of the study, from 6% in the Hamroff
et al., to 55.4% in the most recent CHARM-Added.
Fourthly, the prespecified combined mortality and morbidity endpoint differed between trials. Specifically, the
morbidity element varied significantly. As detailed data to
standardise morbidity was not available, the only unbiased
solution was to use the prespecified combined endpoint
definition.
Finally, as pointed out above, the studies differed in their
distributions of functional classes of the patients. CHARMAdded seems to have included patients with greater degree
of impairment than Val-HeFT and SOLVD. However, this
adds breadth to the range of patients studied.
4.5. Conclusions
There is now satisfactory evidence that patients with
heart failure who are taking ACEi but not h-blockers
would benefit from routine administration of an ARB.
The evidence supporting this is a significant reduction in
combined morbidity – mortality, without evidence of reduced mortality.
For those already taking both ACEi and h-blockers, there
is not convincing evidence of benefit nor of harm from
giving additional ARBs. We are in equipoise for both
mortality and combined morbidity –mortality.
Beta-blockade can no longer be considered a contraindication for combined ACEi-ARB therapy.
Acknowledgements
Dr. Dimopoulos is supported by the European Society of
Cardiology; Dr. Salukhe is supported by the Robert Luff
Fellowship; Dr. Francis was supported by the British Heart
Foundation.
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