23 / 74
CARDIOVASCULAR JOURNAL OF AFRICA • Volume 29, No 6, November/December 2018
AFRICA
355
diuretic significantly decreased during follow up (13% reduction,
p
=
0.0005). Beta-blocker and MRA dosages remained similar
during titration of sacubitril/valsartan.
Symptomatic hypotension, renal dysfunction and hyper-
kalaemia occurred in nine (9%), four (4%) and two patients
(2%), respectively. Sacubitril/valsartan down-titration occurred
in eight patients (8%), and six (6%) had to stop the medication.
Among the causes of discontinuation, one patient underwent
heart transplant and one had hepatitis related to sulfasalazine.
Sacubitril/valsartan was resumed after the patient recovered
from liver injury.
Sacubitril/valsartan was also stopped in two cases for acute
renal failure (associated with hypotension in one patient), one
for symptomatic hypotension and one for dizziness. Among the
patients with symptomatic hypotension, five required sacubitril/
valsartan dose reduction. The sacubitril/valsartan dose was also
decreased in two cases of acute renal failure and one case of
hyperkalaemia.
Discussion
Regarding the primary outcome, the maximal target dose was
reached in 46% of patients. Furthermore, 73% of patients had
a final dose of at least 49/51 mg (100 mg) twice daily. The
PARADIGM-HF study included two single-blind run-in periods
before randomisation, during which patients had to tolerate both
enalapril and sacubitril/valsartan target doses. Around 20% of
patients were excluded after this phase and there is therefore a
possibility that patients selected for the PARADIGM-HF cohort
may differ from the real-world, all-comer population of HF
clinics in 2017, limiting the applicability of its findings outside
research protocols.
In the cohort presented here, 41% of patients had a baseline
ACEI/ARB dose that was inferior or equal to 50% of the target
dose recommended by practice guidelines because of tolerability
issues (blood pressure, dizziness, renal function) or ongoing
titration. These results are quite similar to what has already
been reported in many real-life cohorts.
16,17
In fact, a prospective,
observational trial by Maggioni
et al
. demonstrated that around
92% of HFrEF patients were appropriately treated with an
ACEI/ARB but only 29% were at target doses.
16
Another retrospective cohort from Lenzen
et al
. showed
that among 10 701 patients included in the Euro Heart Survey
on Heart Failure, only 9% would have met inclusion criteria to
be randomised in the SOLVD trial (Study Of Left Ventricular
Dysfunction). Furthermore, even among eligible SOLVD
patients of that real-life cohort, only 41% were actually receiving
target doses of ACEI, as recommended by guidelines.
17
These real-life studies clearly show the existing gap between
clinical trials and implementation in daily practice. This reality
described with ACEI could certainly be transposed to sacubitril/
valsartan. In our cohort, a significant proportion of patients did
not receive ACEI/ARB target doses at baseline and less than
50% of the patients finally reached the maximal dose of the
angiotensin receptor neprilysin inhibitor (ARNI), which is in
accordance with previous real-life trials of HF treatment.
In a recent
post hoc
analysis from PARADIGM-HF, Vardeny
et al
. demonstrated that the need for sacubitril/valsartan dose
reduction during follow up identifies patients with higher
cardiovascular risk. Their findings suggested that patients with
lower doses still benefited from sacubitril/valsartan compared
to lower doses of enalapril.
18
We therefore believe that most of
our patients benefit from titration to the maximal tolerated dose
of sacubitril/valsartan, even if they do not reach the maximal
recommended dose.
The most important secondary outcome of this prospective
study was the safety of sacubitril/valsartan. The incidence of
hypotension and hyperkalaemia in our cohort was lower than
in the original trial. In fact, 9% of patients had symptomatic
hypotension compared to 14% in PARADIGM-HF, and
hyperkalaemia was less frequent (two vs 16.1%). Acute renal
failure episodes were also uncommon (4%). Considering the low
occurrence of adverse events, it appears that our algorithm is
safe and that some patients might tolerate faster titration.
Our study is in accordance with Senni and co-workers’
findings previously published in the TITRATION trial, where a
shorter titration course (three weeks) was shown to be as safe as
a longer titration regimen (six weeks). However, for patients on
lower baseline doses of ACEI or ARB, longer titration helped to
achieve the maximal sacubitril/valsartan dose while minimising
hypotension events.
19
Our study demonstrates that with the use of our titration
algorithm for new ARNI users, the introduction of sacubitril/
valsartan led to a significant reduction in furosemide dosage,
possibly explained by the natriuretic effect of sacubitril/valsartan.
Furthermore, neither down-titration nor discontinuation of
other well-established pharmacological HF treatment occurred.
Overall, patients in our cohort are comparable with the
PARADIGM-HF population. Age, systolic blood pressure,
creatinine level and functional class were similar. As in the
PARADIGM-HF study, most of the patients were on optimal
therapy, but a higher proportion of our patients were using
MRA (71 vs 56%). Mean LVEF was slightly lower in our cohort
(26 vs 30%) and patients were more frequently treated with
cardiac resynchronisation therapy (40 vs 7%) and implantable
cardioverter–defibrillator devices (70 vs 15%).
The study has some limitations. The purpose of this study
was to safely acquire clinical experience with sacubitril/valsartan
initiation and titration. Therefore, selection bias might have
occurred. Death and hospitalisation rates were not analysed in
Table 2. Mean daily dose of heart failure medication during sacubitril/valsartan titration
Mean daily dose
Furosemide (
n
=
80) Metoprolol (
n
=
29) Bisoprolol (
n
=
61) Carvedilol (
n
=
8) Spironolactone (
n
=
59) Eplerenone (
n
=
12)
Baseline, mean
±
SD
(median) (mg)
62
±
53
(40)
93
±
45
(100)
6.0
±
3,3
(5)
45
±
10
(50)
19.7
±
11,0
(12.5)
30
±
13
(25)
Final dose,*
mean
±
SD (median) (mg)
54
±
55
(40)
93
±
45
(100)
5.8
±
3,3
(5)
45
±
10
(50)
19.1
±
11,0
(12.5)
28
±
11
(25)
p-
value**
0.0005
1.0
0.6
1.0
0.31
0.44
*Final dose is the mean daily dose of medication that was taken when the patient reached the maximal tolerated dose of sacubitril/valsartan.
**
p-
values were calculated with mean doses.