European Heart Journal Supplements (2004) 6 (Supplement H), H55–H60
Importance of CHARM in relation to other
heart failure trials with ARBs
Christopher B. Granger*
Duke University Medical Center, Durham, NC 27705, USA
KEYWORDS
AT1 -receptor blockers;
Candesartan;
Clinical trials;
Drug therapy;
Heart failure;
Valsartan
The clinical need for improved heart-failure
therapies
In spite of use of proven therapies, chronic heart failure
continues to be one of the most important causes
of death and disability worldwide. Large randomized
clinical trials have established life-saving benefits
of angiotensin-converting-enzyme (ACE) inhibitors 1,2 ,
b-blockers 3–5 , and spironolactone (for patients with
* Correspondence: Christopher B Granger MD FACC. Duke University
Medical Center, 2400 Pratt Street, Durham, NC 27705, USA. Tel.: +1-919668-8736 fax: +1-919-668-7056.
E-mail address: [email protected]
0169-5002/$ – see front matter
severe heart failure) 6 . ACE inhibitors are especially
impressive in the breadth of evidence of benefit,
with demonstration of survival benefits for patients
following acute myocardial infarction 7 , for secondary
prevention of vascular disease events 8 , and in all
stages of chronic heart failure 1,2,9 . Their particular
benefits in patients with diabetes, including protection
against renal dysfunction 10 , are important since diabetes
and heart failure commonly occur together and their
combination can be a lethal one. B-blockers have
shown impressive additional benefit when added to
ACE inhibitors, with 34–35% relative risk reductions in
death with bisoprolol 3 , extended-release metoprolol 4 ,
and carvedilol 5 . Other b-blockers, however, do not
© 2004 The European Society of Cardiology. Published by Elsevier Ltd. All rights reserved.
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Angiotensin-converting-enzyme (ACE) inhibitors, b-blockers, and spironolactone (for
patients with severe heart failure) have substantially improved survival in chronic
heart failure. Because angiotensin-receptor blockers (ARBs) provide specific and
potent inhibition of the angiotensin type-1 receptor, there has been hope that they
might extend the benefits of ACE inhibitors.
ELITE-II found no benefit with losartan 50 mg a day compared with captopril. In
retrospect, losartan may have been less effective than other ARBs or under-dosed. In
Val-HeFT, valsartan 160 mg twice daily was beneficial in a population where 93% were
on an ACE inhibitor, although subgroup analysis led to speculation that this benefit
was largely restricted to patients not on ACE inhibitors and that addition of valsartan
may have been harmful in patients treated with both ACE inhibitors and b-blockers.
However, no such safety concern with valsartan plus b-blockers was found in the
subsequent VALIANT trial.
CHARM directly addressed the major questions raised by Val-HeFT. In CHARM,
candesartan titrated to 32 mg a day reduced mortality and morbidity both in patients
who were receiving ACE inhibitors and in those intolerant to ACE inhibitors. There was
also substantial benefit in adding candesartan to the combination of ACE inhibitors and
b-blockers. Among patients with low ejection fraction, candesartan resulted in highly
significant reductions in cardiovascular death and heart-failure hospitalization, and in
all-cause mortality. Thus, in patients with low ejection fraction, candesartan improves
survival, regardless of background therapy. Candesartan should now be considered as
another important treatment to further improve outcome in patients with chronic
heart failure.
© 2004 The European Society of Cardiology. Published by Elsevier Ltd. All rights
reserved.
H56
C.B. Granger
Fig. 1. Morbidity and mortality in the Val-HeFT trial. Reproduced with permission from Cohn et al. 2001 16 ; copyright © 2001
Massachusetts Medical Society. All rights reserved.
Previous trials of ARBs
How do ARBs compare to ACE inhibitors?
The promise of ARBs in chronic heart failure was
fuelled by the Evaluation of Losartan in the Elderly
(ELITE) trial 13 , which randomized 722 patients who were
>65 years old to losartan 50 mg a day or captopril 50–
mg three times a day. The primary objective was to
assess effects on renal function, and the drugs resulted
in similar rates of renal dysfunction. However, there was
a 46% relative risk reduction in death at 48 weeks with
losartan, which reached statistical significance. Given
the known unreliability of small trials to estimate effects
on mortality, it should not have been surprising that this
represented an extreme finding.
The first large trial of an ARB in heart failure was
the ELITE-II trial 14 , which was designed to replicate
the first ELITE trial but powered to assess effect on
mortality. The trial enrolled 3152 elderly patients with
chronic heart failure, and there was no impact on
mortality – in fact, the mortality was slightly higher
with losartan (odds ratio (OR) 1.13, 95.7% confidence
interval (CI) 0.95–1.35, p = 0.16). In retrospect, whether
the results were because losartan was underdosed or
because captopril is in fact at least as good as losartan
remains unknown.
Do ARBs add to ACE inhibitors and other proven
treatments?
Because ACE inhibitors may have important benefits
beyond the effects on angiotensin II, including enhancing
bradykinin effects, there is a rationale for combining
ACE inhibitors and ARBs. The RESOLVD trial showed that
the combination of candesartan and enalapril had a
greater impact on limiting remodelling over 43 weeks,
as assessed by change in left-ventricular end-diastolic
volume 15 . The combination caused greater reductions in
both aldosterone and B-type natriuretic peptide than did
monotherapy.
The Val-HeFT trial was designed to address whether
valsartan 160 mg twice daily would improve outcome
when added to contemporary treatments for heart failure
including ACE inhibitors 16 . 93% of patients were on
an ACE inhibitor, and 35% were on a b-blocker.
Valsartan caused a significant ( p = 0.009) 13% relative
risk reduction in mortality and morbidity, a co-primary
endpoint of the trial (Fig. 1). The absolute reduction
was 3.3%, and hospitalization for heart failure was
reduced from 18.2% to 13.8%, a highly significant
(p < 0.001) reduction. Quality of life measures were
also improved with valsartan. All-cause mortality, a
co-primary endpoint, was not affected (OR: 1.02, 95% CI:
0.88–1.18). Subgroup analysis led to speculation that the
benefit of valsartan was largely restricted to patients
not on ACE inhibitors, where the benefit was large. Only
366 patients were in this group, however. Of concern,
post-hoc subgroup analyses showed a 42% increase in
odds of death by adding valsartan among patients treated
with both b-blockers and ACE inhibitors. This led to the
hypothesis that “triple neurohormonal blockade” should
be avoided. Alternatively, it was recognized that this may
have been yet another example of subgroup analyses
providing misleading results due to the play of chance.
CHARM provides answers to questions
raised by Val-HeFT
The CHARM trial was able to address questions raised
by prior trials about the role of ARBs in heart failure.
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appear to have the same degree of benefit 11,12 ,
emphasizing the importance of using proven drugs in
proven doses rather than assuming “class effects”.
Because angiotensin-receptor blockers (ARBs) have the
theoretic advantage over ACE inhibitors of specific,
potent and sustained inhibition of the angiotensin II
type-1 receptor, there has been hope that they might
extend the clinical benefits observed with ACE inhibitors.
Moreover, a substantial portion of patients have
ACE inhibitors discontinued because of intolerance, and
many of those patients might tolerate an angiotensinreceptor blocker.
Importance of CHARM in relation to other heart failure trials with ARBs
H57
Fig. 2. Cardiovascular death or hospitalization for heart failure in CHARM-Alternative. Reproduced from Granger et al. 2003 18 with
permission from Elsevier.
CHARM was designed to assess the role of candesartan
in the broad population of patients with symptomatic
heart failure, including patients with low left-ventricular
ejection fraction (LVEF 40%) not on an ACE inhibitor
due to intolerance (CHARM-Alternative), patients with
low LVEF on ACE-inhibitor therapy (CHARM-Added),
and patients with preserved LV function (CHARMPreserved) 17 . CHARM was different from prior trials in
that the majority of patients were on b-blockers, and
thus the trial was well powered to address whether
there would be risk in using triple therapy. A substantial
proportion – 20% of patients with low LVEF – were also on
spironolactone.
CHARM-Alternative: Does candesartan improve outcome
in chronic heart failure?
In CHARM-Alternative 18 , candesartan titrated to 32 mg
a day significantly reduced cardiovascular mortality and
heart-failure hospitalization among patients intolerant to
ACE inhibitors by 23% (Fig. 2), an effect in the same
order of magnitude as that seen with ACE inhibitors in the
SOLVD trial. In the first year, the 37% mortality reduction
in CHARM 19 was of at least the same order of magnitude
as the 1-year mortality reduction in the SOLVD treatment
trial (23%; Fig. 3). Importantly, the effect in CHARM
was in a population in which the majority were also
on a b-blocker. Thus, CHARM has shown that ARBs,
and specifically candesartan, are highly effective at
improving outcome in heart failure among patients who
do not tolerate ACE inhibitors.
CHARM-Added: does candesartan provide added benefit
on top of ACE inhibitors and b-blockers?
In CHARM-Added 20 , candesartan was added to doses of
background ACE inhibitors that were similar to those
shown to be effective in clinical trials; for example, the
average dose of enalapril in CHARM was 17 mg a day,
similar to the 16 mg a day average in the SOLVD trial. Most
patients (55% at baseline, 66% at trial completion) were
also on b-blockers. In this well-treated population with
chronic heart failure, candesartan provided additional
benefit, with a 15% relative risk reduction ( p = 0.011)
in cardiovascular death and heart-failure hospitalization
over the three years of the trial (Fig. 4). The effect at
1 year was even more significant, showing a 28% relative
reduction in all-cause mortality. There was no safety
concern – on the contrary, there was substantial benefit –
in adding candesartan to ACE inhibitors and b-blockers.
Among patients on ACE inhibitors, the benefit of
candesartan appeared to be at least as great in patients
on baseline b-blockers as in those not on b-blockers.
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Fig. 3. 1-year mortality in CHARM-Alternative 18 and the SOLVD Treatment trial 2 .
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C.B. Granger
Fig. 4. Cardiovascular death or hospitalization for heart failure in CHARM-Added. Reproduced from McMurray et al. 2003 20 with
permission from Elsevier.
Effect of candesartan in patients with low
LV ejection fraction
In CHARM, candesartan resulted in highly significant
reductions in cardiovascular death and heart-failure
hospitalization, and also significantly ( p = 0.018) reduced
(12% relative risk reduction) all-cause mortality among
all patients with low LV ejection fraction 22 .
Other benefits of candesartan
As with valsartan in Val-HeFT, candesartan was found
to improve functional status in CHARM, with significant
improvements in NYHA class overall and in each of the
three component trials 23 . Candesartan was also found to
prevent the onset of diabetes, with an odds ratio of 0.78
( p = 0.02).
How to view VALIANT results in context of CHARM
The VALIANT trial studied a different patient population
than CHARM, namely patients with left-ventricular
dysfunction and/or heart failure in the days following
acute myocardial infarction 24 . The results are generally
consistent with CHARM: valsartan 160 mg twice a day
provided a similar survival benefit to captopril 50 mg
three times a day, and there was no safety concern with
the combination of valsartan and a b-blocker. In VALIANT,
however, the combination of valsartan and captopril,
with titration of valsartan to half the dose combined
with full-dose captopril, was not better than either
monotherapy, and resulted in more adverse effects.
Whether this was due to differences in the patient
populations or the dosing regimens is unclear. The postacute myocardial infarction population is quite different,
with a minority of these patients developing chronic
heart failure. Thus, the direct comparability of CHARM
and VALIANT is limited.
The large trials of ARBs suggest that there is
heterogeneity in the clinical effects of different ARBs
at different doses, such that losartan at 50 mg a day
tended to be worse than captopril in both ELITE-II 14 and
OPTIMAAL 25 . Thus, clinicians should generally use the
drug and the dose proven to be effective in large clinical
trials, in order to have the most confidence of achieving
clinical benefit.
How to manage chronic heart failure patients in light
of recent trials
The incremental benefit of adding effective treatments
for chronic heart failure can make a large impact on
heart-failure morbidity and mortality. To make major
improvements in patient outcome demands systematic
approaches to use a “cocktail” of drugs that when
combined can reduce mortality by over 50%, as
well as improving quality of life. The challenge is
that these treatments can be costly and complex to
titrate and monitor. In patients with low ejection
fraction, the foundation of therapy to improve morbidity
and mortality remains ACE inhibitors (and ARB for
ACE-inhibitor intolerance) and b-blockers, with ARBs
being added for patients with continued symptoms
and low ejection fraction, with attempts to achieve
target dose and monitoring of electrolytes (Fig. 5). For
patients with more severe heart failure, spironolactone
should be added, and digoxin can provide important
improvements in quality of life 26 .
Conclusion
In summary, a series of clinical trials, culminating
in CHARM, have established that ARBs can provide
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As would be expected for any inhibitor of the
renin–angiotensin–aldosterone system, candesartan did
result in excess renal insufficiency and hyperkalaemia.
Therefore, monitoring of electrolytes during initiation
and titration of candesartan is important. In CHARM,
investigators were asked to monitor electrolytes with
each dose titration, which is a prudent approach.
The excess of clinically relevant hyperkalaemia that
has occurred with the adoption of spironolactone for
heart failure in practice 21 reinforces the need to monitor
patients when using any renin–angiotensin–aldosterone
antagonist.
Importance of CHARM in relation to other heart failure trials with ARBs
H59
Fig. 5. Approaches to the patient with heart failure: implications from recent trials.
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