Cardiovascular Journal of Africa: Vol 29 No 6 (November/December 2018)

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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 29, No 6, November/December 2018 352 AFRICA
Usefulness of a titration algorithm for de novo users of
sacubitril/valsartan in a tertiary centre heart failure clinic
Émilie Laflamme, Audrey Vachon, Sylvain Gilbert, Julie Boisvert, Vincent Leclerc, Mathieu Bernier,
Pierre Voisine, Mario Sénéchal, Sébastien Bergeron
Abstract
Background: A reduction in the rate of death and hospitalisa-
tions in patients with heart failure (HF) with reduced ejection
fraction receiving sacubitril/valsartan compared to enalapril
was demonstrated in the PARADIGM-HF study. However,
tolerability when initiating and optimising sacubitril/valsar-
tan treatment in real clinical practice is unknown.
Methods: We performed a prospective cohort study of clinical
and biochemical parameters of the first 100 patients receiving
sacubitril/valsartan in a tertiary HF clinic. Patients had titra-
tion of the molecule guided by an algorithm developed by
pharmacists and cardiologists in the clinic. The objective was
to evaluate the proportion of patients reaching the maximal
dosage, the time to reach maximal dosage, and the rate of
adverse events, as well as the required modification of other
HF therapy during the sacubitril/valsartan titration.
Results: Forty-six per cent of patients reached the sacubitril/
valsartan maximal dose of 97/103 mg (200 mg) twice daily
and 73% received at least 49/51 mg (100 mg) twice daily.
Mean titration time was 30 ± 9 days. Symptomatic hypoten-
sion, renal dysfunction (increase in creatinine level > 30%)
and hyperkalaemia (potassium level > 5.5 mmol/l) occurred
in nine, four and 2% of patients, respectively. Background
HF pharmacological treatment remained stable during the
sacubitril/valsartan titration but daily dosage of furosemide
was reduced by 13% (p = 0.0005).
Conclusions: This algorithm is a safe and easy-to-use tool
in daily clinical practice for the introduction and titration
of sacubitril/valsartan. Almost half of the patients reached
the maximal dose, with a tolerability profile in line with the
original study.
Keywords: heart failure, sacubitril/valsartan, algorithm, titration
Submitted 12/9/17, accepted 24/6/18
Published online 28/8/18
Cardiovasc J Afr 2018; 29: 352-356
DOI: 10.5830/CVJA-2018-039
Heart failure (HF) is one of the most significant healthcare issues
in contemporary medicine. More than a million Canadians are
affected by heart disease and 600 000 are suffering from HF.1
Angiotensin converting enzyme inhibitors (ACEI) were the
first treatment that demonstrated a reduction in the rate of
death, hospitalisations and symptoms in HF in patients with
reduced ejection fraction (HFrEF).2,3 Similar benefits were later
found with beta-blockers4,5 and with mineralocorticoid receptor
antagonists (MRA), in addition to ACEI.6,7 This triple therapy is
nowadays the standard of care for patients with HFrEF. More
than a decade has passed without any significant pharmaceutical
therapeutic innovation besides device implantation for cardiac
resynchronisation therapy8-11 and cardioverter–defibrillator
implantation.12,13
Recently, a combination of sacubitril, a neprilysin inhibitor,
and valsartan, an angiotensin receptor blocker (ARB), was
compared to enalapril in the PARADIGM-HF study.14 In this
trial, the investigators demonstrated an absolute risk reduction
of 4.7% for cardiovascular mortality or first hospitalisation for
HF in patients treated with sacubitril/valsartan compared to
enalapril. Despite hypotension occurring in 14% of the patients,
this new drug proved to be safe. In response to those important
results, Canadian guidelines now recommend changing ACEI
or ARB for sacubitril/valsartan in patients who remain in New
York Heart Association (NYHA) class II–III despite maximal
therapy with ACEI or ARB, beta-blockers and MRAs.15
The purpose of this study was to present real-life clinical
experience and tolerability of sacubitril/valsartan. We describe
the first 100 patients treated with this new drug, titrated
according to an algorithm developed in a tertiary centre HF
clinic.
Methods
A prospective evaluation of the HFrEF patients who were started
on sacubitril/valsartan therapy was conducted at the Institut
Universitaire de Cardiologie et de Pneumologie de Québec
(IUCPQ). Inspired by the PARADIGM-HF and TITRATION
trials, a committee of nine cardiologists and five pharmacists
developed an algorithm to guide initiation and over-the-phone
titration of sacubitril/valsartan (Fig. 1). The first 100 patients
in whom sacubitril/valsartan was initiated were included in this
analysis.
The decision to initiate the drug was left to the treating
cardiologist, but patients had to meet the following criteria:
HFrEF [left ventricular ejection fraction (LVEF) ≤ 40%], systolic
blood pressure of 100 mmHg or more, NYHA class II–
III, potassium level less than 5.4 mmol/l while being on an
ACEI or ARB, and glomerular filtration rate of more than
30 ml/min/1.73m 2. Patients who did not meet those criteria
and those with a previous history of angioedoema, renal
Institut Universitaire de Cardiologie et de Pneumologie de
Québec, Laval University, Quebec, Canada
Émilie Laflamme, MD
Audrey Vachon, BPharm, MSc
Sylvain Gilbert, BPharm, DPH
Julie Boisvert, BPharm, MSc
Vincent Leclerc, BPharm, MSc
Mathieu Bernier, MD, FRCPC
Pierre Voisine, MD, FRCPC
Mario Sénéchal, MD, FRCPC,
Sébastien Bergeron, MD, FRCPC