DRUG TRENDS
SA JOURNAL OF DIABETES & VASCULAR DISEASE
42
VOLUME 8 NUMBER 1 • MARCH 2011
Managing heart failure patients: choosing the best angiotension
receptor blockers
Heart failure registry differentiates between the ARBs, candesartan and losartan
M
ortality in heart failure patients with
impaired left ventricular ejection fraction
(LVEF) was significantly reduced with candesar-
tan in comparison to losartan in a large popu-
lation of patients in everyday care.
1
Fifteen
per cent of the patients in this registry study
of Swedish patients had diabetes; as could be
expected from broad estimations that one in
five diabetic patients will develop heart failure
in the course of their disease.
Heart failure and diabetes are inextricably
linked. Because of this and the high incidence
and financial burden of these conditions, pre-
venting heart failure patients from developing
diabetes; preventing those with diabetes from
developing heart failure; and improving the
prognosis of those with diabetes and heart
failure are important therapeutic goals.
2
Most algorithms for the pharmacological
management of heart failure recommend the
use of an angiotensin II receptor antagonist
(ARB) in ACE-intolerant patients. Currently,
only candesartan and valsartan have evidence
to support their use in heart failure, with posi-
tive outcome data from the CHARM group of
studies when candesartan was used together
with an ACE inhibitor and a
β
-blocker. In con-
trast, valsartan, in the VAL-HEFT study, when
used with an ACE inhibitor and a beta-blocker,
led to an adverse trend of increasing mortality
and morbidity.
3
The positive results for candesartan in this
latest evaluation in a ‘real-world’ situation
were maintained after adjustment for numer-
ous clinical variables, including dose (the com-
parative losartan dose was set at 150 mg/day
in accordance with the HEAAL study
4
), selec-
tion bias and outcome. In the evaluation of
doses in this study, 70% of the candesartan
group received the target dose defined as 32
or 50 mg/day.
The benefit in all-cause mortality with can-
desartan was seen in both the one- and five-
year survival data of patients with a LVEF of
less than 40% and in those with a LVEF of
40% or more. The one-year survival was 90%
for patients receiving candesartan and 83%
for patients receiving losartan. The five-year
survival was 61% for candesartan-treated
patients and 44% for losartan-treated patients.
The hazard ratio (HR) for all-cause mortality
of losartan compared with candesartan was
1.43 overall, and similar in those patients with
impaired LVEF and those with LVEF greater
than 40% (HR of candesartan compared to
losartan was 0.70).
As the patients included in this study were
being treated both in hospital and on an outpa-
tient basis (54.5% of patients), overall mortal-
ity was low (1 329 deaths in the 5 139 patients
included in the analysis). The limitations of
the study relate mainly to its non-randomised
character, yet this real-world situation seems to
reflect and amplify the differences seen in the
randomised clinical trials of these two ARBs.
Candesartan is well known to South African
clinicians following the results of the CHARM
(Candesartan in Heart failure: Assessment of
Reduction in Mortality and Morbidity) ran-
domised clinical trial (RCT) studies published
in 2005.
5,6
In CHARM, analysis of the effects
of candesartan (Atacand) on myocardial infarc-
tion (MI) across the full data set showed that
candesartan significantly reduced the risk of
the primary composite outcome of cardiovas-
cular death or non-fatal MI in patients with
symptomatic heart failure.
7
This study provided
contributory evidence to refute suggestions
that ARBs, unlike ACE inhibitors, may not
reduce myocardial infarction.
8
The findings from CHARM were consist-
ent across all pre-determined subgroups and
across the component CHARM trials (added to
an ACE inhibitor, alternative to ACE inhibitors
and in patients with preserved LVEF), including
patients treated with other therapies proven to
be effective in reducing the risk of MI or re-
infarction.
This analysis of CHARM provided further
support for the benefit of candesartan in this
patient group with New York Heart Association
class II to IV symptoms. The overall CHARM
cohort consisted of 7 599 patients; 4 004 (53%)
had experienced a previous MI, and 1 808
(24%) currently had angina. At baseline, 3 125
(41%) were receiving an ACE inhibitor, 4 203
(55%) a beta-blocker, 3 153 (42%) a lipid-
lowering drug, 4 246 (56%) aspirin, and 6 286
(83%) a diuretic. During the median follow-up
of 37.7 months, the primary outcome of cardio-
vascular death or non-fatal MI was significantly
reduced in the candesartan group (Table 1).
J Aalbers, Special Assignments Editor
1.
Eklind-Cervenka M, Benson L, Dahlstrom U, Edner
M,
et al
. Association of candesartan vs losartan with
all-cause mortality in patients with heart failure.
J
Am Med Assoc
2011;
305
(2): 175–182.
2.
Kirby M. Heart failure and diabetes in primary care.
S Afr J Diabetes Vasc Dis
2007;
4
: 64–69.
3.
Cohn JN, Tognoni G, Valsartan Heart Failure
trial investigators. A randomised trial of the ARB
Valsartan in chronic heart failure.
N Engl J Med
2001;
345
: 1667–1675.
4.
Konstam ME, Neaton JD, Dickstein K,
et al
; HEAAL
investigators. Effects of high-dose versus low-dose
losartan on clinical outcomes in patients with heart
failure (HEAAL study): a randomised, double blind
trial.
Lancet
2009;
374
(9704): 1840–1848.
5.
Granger C, McMurray JJ, Yusuf S,
et al
; CHARM
investigators and committees. Effects of
candesartan in patients with chronic heart failure
and reduced left-ventricular systolic function taking
angiotensin-converting-enzyme inhibitors: the
CHARM-Alternative trial.
Lancet
2003;
362
(9386):
772–776.
6.
McMurray JJ, Ostergren J, Swedberg K,
et al
;
CHARM investigators committees. Effects of
candesartan in patients with chronic heart failure
and reduced left-ventricular systolic function
taking angiotensin-converting-enzyme inhibitors:
the CHARM-Added trial.
Lancet
2003;
362
(9386):
767–771.
7.
Demers C, McMurray JJV,
et al
. Impact of
candesartan on non-fatal myocardial infarction and
cardiovascular death in patients with heart failure.
J
Am Med Assoc
2005;
294
: 1794−1798.
8.
Verma S, Strauss M. Angiotensin receptor blockers
and myocardial infarction.
Br Med J
2004;
329
:
1248−1249.
Table 1.
Effect of candesartan on development of MI, CV mortality and hospitalisation for unstable
angina or coronary revascularisation procedures
Outcome
Candesartan
(
n
=
3 803)
n
, %
Placebo
(
n
=
3 796)
n
, %
p
-value
CV death/non-fatal MI
775, 20.4
868, 22.9
0.004
Non-fatal MI
116, 3.1
148, 3.9
0.03
CV death
691, 18.2
769, 20.3
0.01
Fatal MI, sudden death or non-fatal MI
459, 12.1
522, 13.8
0.02
Sudden death/fatal MI
360, 9.5
394, 10.4
0.11
Hospitalisation, unstable angina
394, 10.4
397, 10.5
0.60
Coronary revascularisation procedures
236, 6.2
241, 6.4
0.50
