Download Sacubitril/valsartan for chronic heart failure: its

■ THERAPY REVIEW
Sacubitril/valsartan for chronic
heart failure: its future potential
STEVE CHAPLIN
NYHA
Symptoms
I
No symptoms and no limitation in ordinary physical activity,
eg shortness of breath when walking, climbing stairs, etc.
II
Mild symptoms (mild shortness of breath and/or angina) and
slight limitation during ordinary activity
III
Marked limitation in activity due to symptoms, even during
less-than-ordinary activity, eg walking short distances
(20–100m)
Comfortable only at rest
IV
Severe limitations in activity
Experiencing symptoms even while at rest
Mostly bedbound patients
Table 1. New York Heart Association (NYHA) functional classification of heart
failure
Sacubitril/valsartan (Entresto),
a combined neprilysin inhibitor/
angiotensin II-receptor antagonist for
the treatment of chronic heart failure
with reduced ejection fraction, was
launched in the UK in January. The phase
3 clinical trial PARADIGM-HF established
its efficacy in chronic heart failure but
what is its future place in therapy,
according to the latest guidelines and
research?
F
ew new drugs enjoy the warm reception accorded to sacubitril/valsartan (Entresto) since publication of the international PARADIGM-HF trial (Prospective Comparison of ARNI
[angiotensin receptor–neprilysin inhibitor] with ACEI [ACE inhibitor] to Determine Impact on Global Mortality and Morbidity in
Heart Failure) in 2014,1 and its subsequent launch in the UK
in January 2016. Many analyses of PARADIGM-HF have been
published since the original trial and new indications are being
explored. So what is the potential of this novel combination of
a neprilysin inhibitor and an angiotensin II-receptor antagonist?
What makes sacubitril/valsartan special?
In a word, PARADIGM. One of the largest trials of a treatment
for heart failure ever conducted, it included 8442 patients
with chronic symptomatic heart failure (mostly New York Heart
Association (NYHA) class II or III – see Table 1) despite taking an ACE inhibitor and a beta-blocker, and with a reduced
ejection fraction averaging about 30 per cent. The double-blind
trial randomised patients to treatment with sacubitril/valsartan
97mg/103mg (200mg) twice daily or the ACE inhibitor enalapril
10mg twice daily (see Figure 1). Sacubitril/valsartan significantly reduced the risk of the primary endpoint (a composite
of death from cardiovascular causes or first hospitalisation for
worsening heart failure) by 20 per cent compared with enalapril
after a median 27 months’ follow-up (see Table 2).1 The trial
was terminated early because an interim analysis showed a significant benefit of sacubitril/valsartan over enalapril. Sacubitril/
valsartan also significantly decreased all-cause mortality, cardiovascular death and the risk of hospitalisation for heart failure,
and improved the symptoms and physical limitations of heart
failure compared with enalapril. It did not reduce the decline in
renal function or the risk of atrial fibrillation.
26 ❚ Prescriber November 2016
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Sacubitril/valsartan
Single-blind run-in period† (6 to 8 weeks)
Median exposure:
15 days (n=10,513)
Enalapril 10mg
twice daily
Double-blind period‡ (actual duration was
event driven)
Median exposure: 29 days (n=9419)
Sacubitril/
valsartan 49/51mg
(100mg) twice daily
l THERAPY REVIEW ■
Sacubitril/valsartan
97/103mg
(200mg) twice daily
Sacubitril/valsartan 97/103mg
(200mg) twice daily (n=4209)
1:1 randomisation
Enalapril 10mg twice daily (n=4233)
†All patients were on an ACE inhibitor or antiotensin II-receptor antagonist prior to the run-in period
‡Median follow-up duration was 27 months; patients were treated for up to 4.3 years
Figure 1. PARADIGM-HF trial design
What else did PARADIGM-HF show?
The many analyses of the PARADIGM-HF data show that sacubitril/valsartan slows heart failure progression compared with
enalapril. Its benefits are consistent despite regional differences in patient populations, there is equal benefit for stable
patients and those recently hospitalised, when outpatient dose
intensification is assessed and regardless of background therapy. It reduces re-admission for any cause within 30 days.
Outcomes were worse after dose reduction during the trial,
with worsening ejection fraction at baseline, higher baseline
risk score and in patients with diabetes or prediabetes, but
efficacy relative to enalapril was unchanged. Sacubitril/valsartan was superior for any cause of death, though differences in
clinical outcomes between the treatment arms were not statistically significant in those aged 75 years and older (see Figure
2) and the incidence of symptomatic hypotension in this age
group was higher with sacubitril/valsartan (18 vs 12 per cent
with enalapril).2
It is estimated that sacubitril/valsartan confers one to two
years of increased life expectancy and survival free from heart
failure for patients like those in PARADIGM-HF.
antagonist – formerly the next step8 – or that they should be
intolerant of an ACE inhibitor.
US guidance specifies a lower symptom severity but is more
explicit, stating: “In patients with chronic symptomatic HFrEF
[heart failure with reduced ejection fraction] NYHA class II or
III who tolerate an ACE inhibitor or ARB [angiotensin II-receptor
antagonist], replacement by an ARNI [angiotensin receptor–
neprilysin inhibitor] is recommended to further reduce morbidity
and mortality”.6
By contrast, the Scottish Intercollegiate Guidelines Network
(SIGN) positions sacubitril/valsartan after the addition of an
aldosterone antagonist and for patients with ejection fraction
≤40 per cent.4 An aldosterone antagonist is considered as
effective as sacubitril/valsartan, though it is an addition to an
ACE inhibitor rather than a substitute. A meta-analysis of eight
trials involving almost 4000 patients showed that adding an
aldosterone antagonist in this way reduces all-cause mortality
(relative risk [RR] 0.79) and admission due to cardiac causes
(RR 0.62).9 In PARADIGM-HF, about half of participants were
taking an aldosterone antagonist but it made no difference to
the efficacy of sacubitril/valsartan.
Place in therapy
Adoption despite qualms
It is clear from the above that there is a lot of evidence for
sacubitril/valsartan, all from one phase 3 trial. It is argued
that the trial was so large and the results so consistent that
the quality of evidence it provides is equivalent to four or five
separate trials.3 This was an innovative treatment, and one
that made a big difference to patients who were symptomatic
despite standard therapy. Consequently, sacubitril/valsartan
has already been incorporated into management guidelines –
but at different steps.4-7
The guidance could hardly be more favourable. NICE recommends sacubitril/valsartan as an option for people with chronic
heart failure and reduced ejection fraction (≤35 per cent) who
have NYHA class II–IV symptoms, despite stable treatment
with an ACE inhibitor or an angiotensin II-receptor antagonist.7
It does not state that patients must be taking an aldosterone
NICE accommodated several reservations about the evidence
when it recommended sacubitril/valsartan. It noted that in participants from western Europe, who were most representative of
patients in the UK, the difference between the treatment arms
in the primary endpoint was not statistically significant (hazard
ratio [HR] 0.89; CI 95% 0.74–1.07). However, NICE decided this
“would not factor in its decision-making”.
Compared with UK practice, participants in PARADIGM-HF
were younger (mean age 64 years), there were only 60 patients
(0.7 per cent) with NYHA class IV symptoms, and fewer were
women (22 per cent), had co-morbidities or used a cardiac
device. Black people were under-represented (5 per cent), which
is important because they are at higher risk of angioedema.10
The dose of valsartan used was higher than some patients tolerate and the ACE inhibitor comparator was enalapril, whereas
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Prescriber November 2016 ❚ 27
■ THERAPY REVIEW l Sacubitril/valsartan
UK clinicians prefer ramipril (though everyone accepted a class
effect was likely). Finally, the trial’s run-in phase included a
period when all participants received sacubitril/valsartan, during which 6.4 per cent withdrew from the study due to adverse
effects or abnormal lab results.1 Selecting patients for tolerability in this way may have reduced the incidence of angioedema
in the trial. Whether these patient differences mean that outcomes in clinical practice differ from those in PARADIGM-HF
remains to be seen.
Uptake so far
Statistics on NHS prescribing are not yet available (and will
have been influenced by the wait for NICE guidance) but
NICE estimates that the number of people taking sacubitril/
valsartan will grow to about 64,500 by 2020/21.11 There
are about 411,000 people with heart failure in England,
of whom 107,000 meet the NICE eligibility criteria for
treatment with the new combination. Within five years it is
expected that 60 per cent of eligible patients will be taking
sacubitril/valsartan (see Figure 3), 34 per cent will have
an ACE inhibitor and the remainder will take an angiotensin
II-receptor antagonist.
Prescribing costs will increase: a year’s treatment with an
ACE inhibitor costs only £32 compared with £1194 for sacubitril/valsartan11 and the estimated cost per quality-adjusted
life year (QALY) saved was “at the upper end of the range that
would normally be considered a cost-effective use of NHS
resources”.7 This will be offset by savings totalling £5.4 mil-
lion per year through fewer hospital admissions, leaving a net
impact of about £70 million annually by 2020/21.
Uptake in Europe is reportedly higher than in the USA,
where sales have been slower than forecast due to administrative obstacles imposed by medical insurance companies and
concerns about cost and long-term safety.12-14 Neprilysin is one
of many pathways for clearing amyloid beta and its inhibition
raises the spectre of Alzheimer’s disease. There’s no evidence
of an increased risk of Alzheimer’s disease so far, but a threeyear trial will begin shortly to compare measures of cognitive
function in patients treated with sacubitril/valsartan or valsartan monotherapy.15
Other heart failure trials
In a move widely interpreted as an attempt to bolster confidence
in sacubitril/valsartan in the USA, Novartis has announced a
new programme of clinical trials, some of which are already
under way. FortiHFy will include 40 trials, generating data on
“symptom reduction, efficacy, safety, quality of life benefits and
real world evidence” in heart failure.16
Most of the success to date has been in patients with
reduced ejection fraction but heart failure with preserved ejection fraction accounts for around half of cases and its prevalence
appears to be growing.17 Treatment is less successful than when
ejection fraction is reduced. Drug treatment focuses on symptom
relief and has not been shown to reduce mortality, morbidity or
improve exercise intolerance.5 PARAGON-HF is a trial comparing
the effects of sacubitril/valsartan and valsartan monotherapy on
Primary endpoint
Sacubitril/valsartan
(% patients)
Enalapril
(% patients)
Hazard ratio (CI 95%)
p value
Death from cardiovascular causes or
first hospitalisation for heart failure
21.8
26.5
0.80 (0.73–0.87)
p<0.001
All-cause mortality
17.0
19.8
0.84 (0.76–0.93)
p<0.001
Cardiovascular death
13.3
16.5
0.80 (0.71–0.89)
p<0.001
First hospitalisation for heart failure
12.8
15.6
0.79 (0.71–0.89)
p<0.001
Death from any cause
17.0
19.8
0.84 (0.76–0.93)
p<0.001
Change in clinical summary score from
baseline to 8 months*
-2.99 ±0.36
-4.63 ±0.36
1.64 (0.63–2.65)
p=0.001
New-onset atrial fibrillation
3.1
3.1
0.97 (0.72–1.31)
p=0.83
Decline in renal function**
2.2
2.6
0.86 (0.65–1.13)
p=0.28
Secondary endpoints
*Kansas City Cardiomyopathy Questionnaire (KCCQ) score (on a scale from 0 to 100, with higher scores indicating fewer symptoms
and physical limitations associated with heart failure); data are least-squares mean ± standard error of the between group difference
**Defined as end-stage renal disease or as a decrease in the estimated glomerular filtration rate (eGFR) of ≥50 per cent or a
decrease of >30ml/min/1.73m2 from randomisation to <60ml/min/1.73m2
Table 2. Primary and secondary outcomes in the PARADIGM-HF trial, comparing sacubitril/valsartan and enalapril in patients with symptoms
of heart failure1
30 ❚ Prescriber November 2016
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Sacubitril/valsartan
cardiovascular death and hospitalisation for heart failure when
added to standard care (excluding ACE inhibitors and angiotensin II-receptor antagonists) in patients with preserved ejection
fraction.18 Patients are ≥55 years of age with left ventricular
ejection fraction ≥45 per cent who need treatment with a diuretic
to relieve NYHA class II–IV symptoms. Follow-up will be four to
five years and results are expected in 2019.
A 12-week phase 2 trial in patients with preserved ejection
fraction (PARAMOUNT, n=266) showed that, compared with valsartan monotherapy, sacubitril/valsartan reduced N-terminal
pro B-type natriuretic peptide (NT-proBNP; the primary endpoint,
a marker of left ventricular wall stress)19 and this was independent of the greater reduction in systolic blood pressure.20
PARADISE-MI is testing the hypothesis that sacubitril/
valsartan can reduce cardiovascular death, hospitalisation for
heart failure and new-onset heart failure in patients at high risk
of heart failure after a myocardial infarction.21 Ramipril is the
comparator; completion is expected in 2020. A trial in Ireland
is also looking at prevention by comparing the effects of sacubitril/valsartan with valsartan alone on left ventricular diastolic
function in people with hypertension, diabetes or other risk
factors for heart failure.22
Other trials in people with hear t failure include
TRANSITION, which is comparing initiation of sacubitril/valsartan before or after discharge in patients admitted with
acute decompensation;23 and PIONEER-HF, a comparison with
enalapril of the effects of sacubitril/valsartan treatment on
NT-proBNP in stable patients admitted for acute decompensated heart failure and reduced ejection fraction.24 Results
for both are expected in 2018.
Cardiovascular death
Cardiovascular death or heart failure
hospitalisation
18
18
12
10
8
6
4
2
sacubitril/valsartan
14
12
10
8
6
4
2
0
0
<55 55-6465-74 ≥75
Age (years)
Heart failure hospitalisation
18
<55 55-6465-74 ≥75
Age (years)
All-cause death
18
16
Rate per 100 patient years
16
Rate per 100 patient years
enalapril
16
Rate per 100 patient years
Rate per 100 patient years
16
14
l THERAPY REVIEW ■
14
12
10
8
6
4
2
14
12
10
8
6
4
2
0
0
<55 55-6465-74 ≥75
Age (years)
<55 55-6465-74 ≥75
Age (years)
Figure 2. Clinical outcomes with sacubitril/valsartan vs enalapril in PARADIGM-HF according to age (rate per 100 patient-years of treatment;
error bars are 95% confidence intervals). Reproduced from Jhund et al. 20152
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■ THERAPY REVIEW l Sacubitril/valsartan
People with heart failure in England
410,783
295,764
Reduced ejection fraction
Reduced ejection fraction and NYHA class II–IV
symptoms
210,288
Reduced ejection fraction ≤35 per cent and NYHA
class II–IV symptoms
Reduced ejection fraction ≤35 per cent and NYHA
class II–IV symptoms and taking an ACE inhibitor/
angiotensin II-receptor antagonist
People taking sacubitril/valsartan from year five
onwards
125,121
107,541
64,525
Figure 3. Number of people with heart failure in England, proportion eligible for treatment and predicted proportion treated with sacubitril/
valsartan in five years’ time11
Use in hypertension
In PARADIGM-HF, sacubitril/valsartan was associated with
a greater reduction in systolic blood pressure than enalapril
(3.2mmHg) and symptomatic hypotension was significantly
more common (14.0 vs 9.2 per cent respectively).1 Its therapeutic potential in hypertension has since been evaluated in
many trials (see Clinicaltrials.gov for a full list), suggesting a
greater blood pressure-lowering effect than valsartan alone or
olmesartan and efficacy as add-on therapy when amlodipine
has failed.
A recent review assessing the efficacy and safety of sacubitril/valsartan in hypertension suggests that the effect on blood
pressure is greater in Asian patients than Caucasian patients
and treatment is well tolerated, though the risk of orthostatic
hypotension requires further study.25 The authors of this review
speculate that sacubitril/valsartan may offer greater efficacy
and a similar safety profile compared with established anti­
hypertensive drugs.
The results of the PARAMETER trial in elderly people with
systolic hypertension were reported recently.26 Compared with
the angiotensin II-receptor antagonist olmesartan, once-daily
sacubitril/valsartan significantly reduced measures of aortic stiffness (including aortic systolic pressure and pulse pressure) at
12 weeks but not after 52 weeks. It is rumoured that Novartis
will not pursue marketing authorisation for hypertension.27
Use in chronic kidney disease
Inhibition of neprilysin causes natriuresis and reduces intra­
glomerular pressure and proteinuria. This, in combination with
inhibition of the renin-angiotensin system, indicates obvious
potential for sacubitril/valsartan in the treatment of chronic kidney disease (CKD).28 Supported by indirect evidence from clinical trials of other neprilysin inhibitors, the effect of sacubitril/
valsartan in CKD is now being evaluated in the UK Heart And
Renal Protection III (UK HARP-III) trial (http://www.harp3trial.
32 ❚ Prescriber November 2016
org). This Oxford-based trial is comparing sacubitril/valsartan
with the angiotensin II-receptor antagonist irbesartan as monotherapy in patients with proteinuric CKD. The primary endpoint
is the change in glomerular filtration rate after 12 months.
Recruitment is now complete (n=414).
Other neprilysin inhibitors in development
Several neprilysin inhibitors have been in development over the
past 30 years but only sacubitril (in combination with valsartan)
has successfully reached the market.29 Interest in this class of
agents appears to have stalled in the early to mid-2000s and
there is surprisingly little information in the public domain about
forthcoming neprilysin inhibitors.
Therevance Biopharma has TD-0714 and TD-1439 in
phase 1 development for heart failure and CKD30, but otherwise Novartis appears to have the market to itself for the near
future. Solvay Pharmaceuticals was developing daglutril, a dual
inhibitor of neprilysin and endothelin-converting enzyme that
has been shown to lower blood pressure in people with type 2
diabetes, nephropathy and hypertension,31 but no studies have
been published more recently.
Summary
Sacubitril/valsartan is an innovative treatment for heart failure
that improves symptoms and reduces the risk of death and
hospital admission compared with ACE inhibitor therapy – the
standard for many years. It has generated huge enthusiasm
among specialists and has already found a place in management guidelines. There are differences between UK patients
with heart failure and the participants in the clinical trial on
which its reputation is built but it is not yet known if they are
important. More clinical trials will refine its role, especially in
patients with heart failure and preserved ejection fraction and
in CKD, but a licence for hypertension looks unlikely in the near
future.
prescriber.co.uk
Sacubitril/valsartan
References
1. McMurray JJ, et al. Angiotensin-neprilysin inhibition versus enalapril
in heart failure. N Engl J Med 2014;371:993–1004.
2. Jhund PS, et al. Efficacy and safety of LCZ696 (sacubitril-valsartan) according to age: insights from PARADIGM-HF. Eur Heart J
2015;36:2576–84.
3. Jhund PS, McMurray JJ. The neprilysin pathway in heart failure: a review and guide on the use of sacubitril/valsartan. Heart
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4. Scottish Intercollegiate Guidelines Network. Management of chronic
heart failure. SIGN 147. March 2016. http://www.sign.ac.uk/pdf/
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5. Ponikowski P, et al. 2016 ESC Guidelines for the diagnosis and treatment
of acute and chronic heart failure. Eur Heart J 2016;37(27):2129–2200.
6. Yancy CW, et al. 2016 ACC/AHA/HFSA focused update on new pharmacological therapy for heart failure: An update of the 2013 ACCF/
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failure with reduced ejection fraction. TA388. April 2016. https://www.
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with mild to moderate chronic heart failure: a systematic review and
meta-analysis. Br J Clin Pharmacol 2013;75:1202–12.
10. Gibbs CR, et al. Angioedema due to ACE inhibitors: increased risk in
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POEMs
In patients with type 2 diabetes and cardiovascular disease, empagliflozin reduces
cardiovascular and all-cause mortality
Clinical question:
In patients with type 2 diabetes and cardiovascular disease, does the addition
of empagliflozin improve outcomes?
Study design: Randomised controlled
trial (double-blinded). Funding source:
Industry. Allocation: Concealed.
Setting: Outpatient (any).
Bottom line:
In patients with established cardiovascular disease and type 2 diabetes, the
addition of empagliflozin to standard
therapy reduces all-cause mortality and
cardiovascular mortality. This is notable
because empagliflozin is the only drug
other than metformin to demonstrate a
mortality benefit, albeit for a fairly narrow group of patients. A dose of 10mg
appears to provide a similar benefit to
the 25mg dose, but with half the risk of
genital infections. It is not appropriate to
extend these conclusions to all patients
with type 2 diabetes, as they are at lower
risk of bad outcomes and are unlikely to
benefit to the same degree. (LOE = 1b)
Synopsis:
Empagliflozin decreases reabsorption of
glucose in the kidneys, leading to greater
urinary excretion. In this industry-sponsored trial, adults with type 2 diabetes
and known cardiovascular disease were
randomised to receive either empagliflozin 10mg, empagliflozin 25mg, or placebo. The 7028 patients were recruited
from 590 sites in 42 countries. The
mean age of participants was 63 years,
71 per cent were male, and 5 per cent
were African-American. This was a very
high-risk group: 75 per cent had coronary
artery disease, 23 per cent had a previous stroke, 20 per cent had peripheral
arterial disease and 25 per cent had a
coronary artery bypass graft. The other
diabetes medications used by patients
included metformin (75 per cent), insulin
(53 per cent) or a sulfonylurea (43 per
cent). Analysis was by modified intention
Reference:
Zinman B, et al, for the EMPA-REG
OUTCOME Investigators. N Engl J Med
2015;373(22):2117–28.
prescriber.co.uk
to treat for all patients who received at
least one dose of the study drug. The
primary outcome was a composite of
myocardial infarction (MI), stroke or cardiovascular death. Patients were followed
up for a median of 3.1 years. Results for
the two empagliflozin doses were pooled
and compared with placebo.
The patients in the intervention
groups had lower all-cause mortality (5.7
vs 8.3 per cent; p<0.001; number needed
to treat [NNT] = 38 over 3.3 years), cardio­
vascular mortality (3.7 vs 5.9 per cent;
p<0.001; NNT=45 over 3.3 years), and
hospitalisation for heart failure (2.7 vs
4.1 per cent; p=0.002, NNT=71). There
were no differences in other outcomes,
including MI, stroke, coronary revascularisations or transient ischaemic attacks.
The pooled dropout rate due to adverse
events was 11.5 per cent for the study
drug and 13.0 per cent for placebo. There
were more episodes of urosepsis or pyelo­
nephritis in the empagliflozin groups (0.8
vs 0.5 per cent), and far more genital
infections (5.0 vs 1.5 per cent in men;
10.0 vs 2.6 per cent in women).
Prescriber November 2016 ❚ 33
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Declaration of interests
None to declare.
Steve Chaplin is a pharmacist who specialises in writing on
therapeutics
34 ❚ Prescriber November 2016
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