Download The use of BNP to monitor and guide treatment of heart failure patients

Health Policy Advisory Committee on
Technology
Technology Brief
The use of BNP to monitor and guide treatment of heart
failure patients
August 2012
© State of Queensland (Queensland Health) 2012
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TECHNOLOGY BRIEF
Register ID
WP123 (NZ referral)
Name of Technology
B-type natriuretic peptide (BNP) assay
Purpose and Target Group
To monitor and guide the treatment of heart
failure patients
Stage of Development in Australia

Yet to emerge

Established

Experimental

Established but changed indication
or modification of technique

Investigational

Should be taken out of use

Nearly established
Australian Therapeutic Goods Administration Approval

Yes

No

Not applicable
ARTG number
International Utilisation
COUNTRY
LEVEL OF USE
Trials underway or
completed
Limited use
Widely diffused
New Zealand
France
USA
Switzerland
Impact summary
A number of companies manufacture immunoassays for the detection of either brain
(or B-type) natriuretic peptide (BNP) or the inactive N-terminal proBNP including
Roche Diagnostics (Elecsys® pro-BNP), Abbott Diagnostics (AxSYM® BNP) and Alere
Triage® BNP Test (formerly Biosite Inc). In vitro diagnostic medical devices (IVDs),
such as these immunoassays, are currently not required to be registered on the
Australian Register of Therapeutic Goods; however, under the TGA regulatory
framework introduced in July 2010, IVDs will be required to be registered as of July
2014. Since July 2008, a Medicare Benefits Schedule item number (66830) has
existed for the “Quantitation of BNP or NT-proBNP for the diagnosis of heart failure
in patients presenting with dyspnoea to a hospital Emergency Department”. This
BNP to monitor and guide treatment of heart failure patients: August 2012
1
Brief is intended to assess the current safety and effectiveness evidence for the use
of BNP assays to monitor and guide treatment in patients already diagnosed with
heart failure.
Background
Heart failure (HF) is a common condition with an incidence and prevalence that
increases with age. HF occurs when heart function is impaired causing the heart to
pump blood less efficiently around the body. HF may be caused by a number of
diseases or conditions that impair or overload the heart, including hypertension,
ischaemic heart disease or cardiomyopathy. Symptoms of severe heart failure
include chronic tiredness and dyspnoea or shortness of breath at rest or on exertion.
HF results in irreversible damage to the heart muscle and, as such, is generally
considered to be life-threatening and associated with poor survival.1 Systolic HF,
where the heart fails to effectively contract in systole, is the most common cause of
chronic HF. Diastolic HF, which is more common in the elderly, retains systolic
function and is indicated by the impairment of left ventricle filling during diastole. 2
There are two types of cardiac natriuretic peptides secreted by the heart: atrial
(ANP) and brain (BNP). BNP is secreted constitutively from myocytes, with secretion
increasing in response to pressure and volume overload in the ventricles, such as
that noted to occur in heart failure patients. Two forms of BNP circulate in the
plasma, BNP-32 and the inactive pro-hormone N-terminal fragment BNP (NTproBNP). The natriuretic peptides bind to, and mediate, activity via receptors found
in a number of tissues, including the kidneys, brain, heart and the adrenal glands in
addition to the vasculature. The physiological effects of the natriuretic peptides are
varied including inhibition of neural-hormonal over-activation, relaxation of vascular
and pulmonary smooth muscle, and the inhibition of cardiac hypertrophy and
ventricular fibrosis. In addition, the peptides may cause lipolysis, increase the
permeability of the endothelial vasculature and reduce intravascular volumes.3, 4
Normal plasma levels of BNP and NT-proBNP are 7.4 ng/L (range 5-50.3 ng/L) and
36.6 ng/L (range 7-163 ng/L), respectively. When used as a diagnostic tool, reported
cut-off values for BNP or NT-proBNP vary according to presenting symptoms and age
(Table 1), with levels affected by underlying conditions such as renal failure
(increased levels), obesity (falsely low levels) and atrial fibrillation (higher than
expected levels) (clinical feedback). Most authors agree that a cut-off level of 100
ng/L of BNP has a strong negative predictive value, ruling out a diagnosis of heart
failure.3, 5 Although BNP and NT-proBNP are secreted in equi-molar proportions, the
half-life of BNP is short (20 minutes) compared to NT-proBNP (120 minutes),
therefore NT-proBNP is more often used for diagnostic purposes. In addition, the
two peptides are cleared from the circulation using different pathways, with NTproBNP cleared via renal excretion only and BNP cleared using a combination of
BNP to monitor and guide treatment of heart failure patients: August 2012
2
receptors, renal excretion as well as neutral endopeptidases (NEP).4, 6 In its current
form, a BNP test acts as a tool to triage patients presenting to emergency
departments. BNP testing is designed to rule out, rather than rule in, patients with
HF. Patients testing positive for BNP, and therefore possibly HF, will undergo further
diagnostic workup.7 A BNP value of <100 ng/L has a 96 per cent probability of
excluding the diagnosis of HF, however, it is unlikely that BNP would be used to
triage all patients, just those in whom a clinical diagnosis of HF is uncertain. 8
Table 1
Cut-off values for the diagnosis of heart failure using BNP or NT-proBNP
Rule out: HF
unlikely
Rule in: HF likely
BNP (ng/L)
100
500
NT-proBNP (ng/L), age <50 years*
300
450
NT-proBNP (ng/L), age >50 years*
300
900
NT-proBNP (ng/L), age <75 years**
125
NT-proBNP (ng/L), age >75 years**
450
* In patients presenting with dyspnoea (Weber and Hamm, 2006), ** Rademaker et al (2005)
The level of BNP or NT-proBNP in the plasma directly relates to the severity of HF
symptoms and is often associated with a worse patient prognosis. As described in
Figure 1, increasing levels of BNP correlate with disease severity as assessed by the
New York Heart Association (NYHA) functional class1.5 BNP has been demonstrated
to be a strong predictor of cardiovascular and all-cause mortality. As such, levels of
BNP may act as a prognostic tool that is independent of, and more accurate than,
NYHA class and left ventricular eject fraction (LVEF).3, 4
Figure 1
1
Median BNP in patients with heart failure according to New York Heart
Association (NYHA) functional status criteria (Weber and Hamm, 2006)
See comparator section
BNP to monitor and guide treatment of heart failure patients: August 2012
3
In addition to being used for the diagnosis and prognosis of HF patients, the cardiac
peptides may also be beneficial in the treatment of certain HF patients with
symptoms featuring volume overload and vasoconstriction. Two approaches have
been used in the treatment of HF patients with BNP: administration of synthetic BNP
or the use of NEP inhibitors, which increases the levels of endogenous BNPs by
blocking their enzymatic breakdown.3
In June 2004, HealthPACT completed a report on the use of pro-BNP for the
diagnosis of congestive heart failure9. MSAC conducted a full HTA on the use of BNP,
Part A of which, the use of BNP in the hospital emergency setting, was finalised in
November 2006 with the MSAC recommended public funding for this indication. Part
B of which, the use of BNP assays in the diagnosis and monitoring of heart failure in
the primary care setting, was finalised in May 2007, with public funding not
supported by the MSAC. In the case of Part B, the MSAC recommended further
research to identify appropriate usage and the patient group most likely to benefit in
the non-hospital setting.7 Although a number of studies were identified that
documented the use of BNP to monitor heart failure patients placed on
pharmaceutical interventions, none of these studies reported on direct patient
benefits, such as increased survival. Only two studies were identified for inclusion in
the assessment of monitoring heart failure (HF) patients, one of which was a welldesigned, albeit small (n=69), randomised controlled trial conducted in New
Zealand.10 This landmark trial reported that monitoring HF patients using a NTproBNP assay resulted in fewer cardiovascular deaths and total cardiovascular events
than HF patients monitored using clinical criteria alone. Since the publication of the
MSAC report, a number of studies have described the use of BNP testing to monitor
the efficacy of treatment for HF patients.
Pharmacological therapy for HF patients usually involves a combination of diuretics,
β-blockers and ACE2 inhibitors. High doses of diuretics may impact negatively on
renal function; however, a failure to remove fluid may result in recurrent congestion
and re-hospitalisation. Therefore, the clinical goal for HF treatment is to reduce or
resolve congestion while minimising hypotension and renal dysfunction.11 As a result
of effective treatment of HF, a reduction in the circulating levels of natriuretic
peptides will be observed, which in turn correlates with improvements in clinical
symptoms and haemodynamic function, and with an associated reduction of
morbidity and mortality. Persistently high levels of natriuretic peptides, despite
appropriate treatment, are indicative of patients who are at high-risk of adverse
outcomes. It has been postulated that regular, serial measurements of BNP may be
2
ACE inhibitors = angiotensin-converting enzyme inhibitors block the angiotensin pathway, increasing
vasodilation and in so doing decreases arterial pressure. In addition, the excretion of sodium and water
via the kidneys is increased, reducing blood volume, and venous and arterial pressure.
BNP to monitor and guide treatment of heart failure patients: August 2012
4
used as a tool to guide HF therapy, in particular, using BNP measurements as a guide
to achieving optimal pharmacotherapy by titrating therapies.3 By optimising therapy,
it is hoped that the number of re-hospitalisations of HF failure patients will be
reduced, further reducing overall costs associated with HF. The measurement of NTproBNP should be used in patients where synthetic BNP is being administered as a
treatment option.3
Although there are several BNP/NT-proBNP assays on the market, they are all
essentially in vitro immunoassays, designed to be used on plasma, serum or whole
blood. Most commercial assays use the basic principle of using antibodies to bind to
BNP or NT-proBNP, followed by a detection step. The RAMP ® NT-proBNP assay,
manufactured by Response Biomedical Corporation (Canada), can be used on whole
blood and is a quantitative immunochromatographic assay, however this assay is not
used in Australia. Test strips, impregnated with antibodies to NT-proBNP bound to
fluorescent-dyed latex particles, are placed in the sample. Any NT-proBNP present
will bind to this complex, emitting fluorescence proportional to its concentration. 12
Most BNP assays are designed to be used on plasma and are sandwich
immunoassays. Two antibodies are used to bind to BNP, with one biotinylated
antibody bound to streptavidin magnetic particles for detection. 13
Clinical Need and Burden of Disease
Based on the 2007-08 national health survey, 277,800 Australians or 1.4 per cent of
the population had self-reported HF failure or oedema, with females reporting
higher disease prevalence (1.7%) than males (1.0%). Prevalence of HF increased with
age from 2.6 to 8.2 per cent in people aged 55-64 and >75 years, respectively.14
Based on the 2004-05 National Aboriginal and Torres Strait Islander Health Survey,
approximately one per cent, or 4,500, of indigenous Australians have HF: a
prevalence rate that is 1.7 times higher than for non-indigenous Australians when
adjusted for age. Differences in prevalence rates can also be observed in rural and
remote areas, and between different socio-economic groups.1
In the year 2009-10 there were 45,004 and 4,054 public hospital separations for the
principal diagnosis of heart failure (ICD-10 code I50) and cardiomyopathy (ICD-10
code I42), respectively. The majority of these separations were for congestive HF
(36,158 or 80%) and dilated cardiomyopathy (1,865 or 46%). The average length of
stay for cardiomyopathy and HF was five and seven days, respectively. The
overwhelming majority of HF separations were for individuals aged over 70 years of
age (36,054 or 80%), whereas 67 per cent of separations (2,718) for cardiomyopathy
were in individuals aged ≥50 years.15 The number of public hospital separations for
HF has remained steady over the past 10 years.14
BNP to monitor and guide treatment of heart failure patients: August 2012
5
In 2007, HF was the attributable cause of death in 4,055 individuals, however, due to
the complex nature of the disease it was also listed as the underlying or associated
cause of death in 19,967 cases. The majority of deaths (90%) occurred in people
aged over 75 years. Over the past 20-years, the age-standardised death rate for
heart failure has fallen markedly from 38 to 17 deaths per 100,000, however, this
rate is much higher when heart failure and underlying and associated causes of
death are taken into account (approximately 85.8 per 100,000).1, 14
The use of pharmaceutical agents may give an indication as to the number of
patients who may progress to HF and, therefore require monitoring with BNP assays.
ACE inhibitors may delay the development of symptomatic chronic HF in patients
with asymptomatic left ventricular dysfunction and beta-blockers, when
administered early post-myocardial infarction may reduce the subsequent
development of chronic HF in patients with preserved ventricular function. In
addition, other anti-hypertensive medications may reduce blood pressure and
reduce the incidence of CHF.2 In Australia during 2007-08, 3.8 million patients filled
in excess of 70 million PBS-subsidised prescriptions for medicines to prevent or treat
cardiovascular disease, an increase of 8.2 per cent over the period 2004-05. During
this period 838,427 patients had 5.8 million prescriptions for beta-blockers
dispensed, 2 million patients filled 20.8 prescriptions for ACE inhibitors and 173,854
patients had 846,068 prescriptions dispensed for anti-hypertensive medication.14
In New Zealand there were 8,426 and 685 public hospital discharges for HF and
cardiomyopathy, respectively, during the year 2009-10. The average length of stay
was 18.6 days for HF patients compared to 5.6 days for those patients admitted with
cardiomyopathy. Although numbers of female and male patients were similar, the
average length of stay for females with HF was considerably longer than that for
males (24.1 days vs 13.4 days). In the private system there were only eight
separations for cardiomyopathy with an average length of stay of 11.2 days.
Although there were only 132 separations in the private system for HF, the average
length of stay was 146.4 days.16 In 2009, there were a total of 10,372 deaths from
diseases of the circulatory system in New Zealand. Of these 170 were attributable to
cardiomyopathy, with the majority of these deaths occurring in males (73.5%).
Conversely, 293 deaths were attributable to HF, the majority of which occurred in
females (66.9%).17
Diffusion of technology in Australia
The use of BNP assays for the diagnosis of HF is in widespread use in Australia. It was
difficult to ascertain the status of BNP testing in New Zealand due to each District
Health Board having different schedules for diagnostic tests.
BNP to monitor and guide treatment of heart failure patients: August 2012
6
In Australia during 2011, the number of services performed using the MBS item
number 66830 to diagnose heart failure was 6,061, however, this is only indicative of
the number of services provided in private, rather than public hospitals where it
would be expected that the number of services would be much higher.18
Comparators
Commonly used monitoring tools include clinical evaluation, which may involve
functional capacity assessment; fluid status; cardiac rhythm; and circulating levels of
urea, electrolytes and creatinine. Functional capacity may be measured by quality of
life questionnaires, exercise tests such as the 6-minute walk or maximal exercise
test, and peak VO2 consumption. Fluid states are measured by physical examination
such as assessing body weight, blood pressure and jugular venous distension; and
cardiac rhythm is assessed by an electrocardiogram.19 The severity of HF may be
classified according to the New York Heart Association Classification (NYHA) system
(Table 2).
Table 2
Assessment of heart failure patients using the NYHA classification criteria
Class
New York Heart Association Classification
I (mild)
No limitation of physical activity. Ordinary physical activity does not cause undue
fatigue, palpitation, or dyspnoea
II (mild)
Slight limitation of physical activity. Comfortable at rest, but ordinary physical
activity results in fatigue, palpitation, or dyspnoea.
III (moderate)
Marked limitation of physical activity. Comfortable at rest, but less than ordinary
activity causes fatigue, palpitation, or dyspnoea.
IV (severe)
Unable to carry out any physical activity without discomfort. Symptoms of cardiac
insufficiency at rest. If any physical activity is undertaken, discomfort is increased.
5
Safety and Effectiveness
Several randomised controlled trials (RCTs) reporting on the use of BNP or NTproBNP for guiding treatment of HF were identified for inclusion in this Brief,11, 20-22
however, two meta-analyses of RCTs were later identified via pearling of the
references in these papers.23, 24
The meta-analysis by Felker et al (2009) included six studies, all of which, bar the
STARBRITE trial11, were included in the meta-analysis of eight studies by
Porapakkham et al (2010). Therefore, only the results from the latest meta-analysis
will be reported here (level I intervention evidence). The STARBRITE3 trial was
3
In brief, the STARBRITE trial enrolled 137 patients admitted to hospital with acute HF, a LVEF
≤35% who were NYHA class III/IV on admission, randomised to usual care (n=69) or BNP guided
care (n=68). Patients were placed on medication, including ACE inhibitors, β-blockers etc, according to
their needs; however, only diuretic therapy was adjusted or titrated during follow-up visits. Diuretics
were adjusted according to BNP levels in the BNP group or by clinical symptoms in the UC group. At
90 day follow-up, there was no significant difference in the number of days alive and not hospitalised
(hazard ratio 0.72, 95% CI [0.41, 1.27], p=0.25) between the two groups. This may have been due to a
BNP to monitor and guide treatment of heart failure patients: August 2012
7
excluded from this meta-analysis on the grounds that it was only reported in a single
study. Two studies were included using results presented at conference meetings:
the PRIMA4 and SIGNAL-HF5 studies. Characteristics of the individual studies are
summarised in Table 4.
Of the eight studies included in the meta-analysis, three would be considered small,
with 20 to 36 patients in each arm. The majority of the remaining studies were
medium to large sized RCTs (110 to 250 patients in each arm). In total, results from
1,726 patients were pooled for analysis. The results from all of the individual studies
and the overall risk ratio are summarised in Table 3. Overall, the all-cause mortality
was lower in patients whose post-discharge HF treatment was guided by the use of
BNP compared to those patients who received usual care (RR= 0.76, 95% CI [0.63,
0.91], p=0.003). There was no significant heterogeneity between the trials, with a χ 2
value of 3.81 (p=0.80), however there was variation between the studies in respect
to the type of assay used (BNP and NT-BNP), the cut-off values used and the
medications used when treatment was guided by BNP. The TIME-CHF trial
dominated the effect, contributing 49.6 per cent of the weight. Two trials, the TIMECHF and BATTLESCARRED trials, stratified randomisation by age, providing data on
patients younger than 75 years or 75 years or older. A sub-group analysis found that
all-cause mortality in patients <75 years with HF treatment guided by BNP testing
was lower (RR= 0.52, 95% CI [0.33, 0.82], p=0.005) compared with patients treated
with usual care (heterogeneity χ2 =0.57, p =0.45). There was no significant difference
between the two groups when all-cause mortality was assessed for those aged >75
years (RR = 0.94, 95% CI [0.71, 1.25], p= 0.70, heterogeneity χ2 = 1.14, p =0.29). Only
three studies provided data on all-cause hospitalisation. There was no significant
difference between the intervention and usual care groups for this outcome (RR =
0.82, 95% CI [0.64, 1.05], p= 0.12). This analysis was dominated by the STARS-BNP
study, which contributed 80.4 per cent of the weight. Similarly, there was no
significant difference between the two groups for the outcome of survival free of any
hospitalisation, however, this outcome was only reported by two studies (RR = 1.07,
95% CI [0.85, 1.34], p= 0.58).
number of factors including small sample size, inadequate length of follow-up and the fact that only
diuretic medication was adjusted in response to BNP measurements.
4
PRo-brain-natriuretic peptide guided therapy of chronic heart failure IMprove heart failure morbidity
and mortality Study. Paper presented at: Annual Scientific Meeting of American College of
Cardiology; March 29, 2009; Orlando, Florida.
5
SIGNAL-HF Study. Paper presented at the European Heart Failure Association Annual Meeting;
June 1, 2009; Nice, France.
BNP to monitor and guide treatment of heart failure patients: August 2012
8
Table 3
Summary of outcome measures comparing BNP-guided HF treatment to
usual care
All-cause mortality
Risk ratio [95% CI]
All-cause
hospitalisation
Risk ratio [95% CI]
Troughton et al
0.16 [0.02, 1.20]
0.69 [0.31, 1.58]
Beck-da-Silva et al
0.48 [0.05, 4.85]
0.48 [0.10, 2.32]
Esteban et al
1.25 [0.37, 4.21]
STARS-BNP
0.64 [0.26, 1.58]
TIME-CHF
0.75 [0.58, 0.96]
BATTLESCARRED
1.00 [0.45, 2.22]
PRIMA
0.79 [0.57, 1.10]
SIGNAL-HF
0.79 [0.22, 2.86]
Overall
0.76 [0.63, 0.91]
Survival free of
hospitalisation
Risk ratio [95% CI]
1.06 [0.69, 1.62]
0.87 [0.67, 1.12]
1.07 [0.82, 1.38]
0.82 [0.64, 1.05]
1.07 [0.85, 1.34]
An informal analysis of two studies: the PRIMA and the excluded STARBRITE study,
reported that the number of days patients were alive and not hospitalised was
slightly higher in the BNP-guided treatment group compared to usual care, however
this difference did not reach significance in either study (85 ± 12.1 (BNP) vs
80.4 ± 20.6 (UC) days and 685 (BNP) vs 664 (UC) days in the STARBRITE and PRIMA
studies, respectively).
The STARS-BNP and PRIMA studies reported the number of patients in whom
medical treatment was adjusted (Figure 2A). Patients in the BNP-guided group had
their medications adjusted more than those who received usual care, with the
difference reaching significance for diuretics, ACE inhibitors and β-blockers. The
STARS-BNP and TIME-CHF studies also reported that significantly more patients in
the BNP group reached their target medication doses (Figure 2B).
Figure 2
24
Medical treatment adjustment
A: percentage of patients having doses of medication increased
B: percentage change of patients reaching target dose
BNP to monitor and guide treatment of heart failure patients: August 2012
9
Table 4
Patient characteristics and study overview of the included trials
Troughton et
10
al
Beck-da25
Silva
Esteban et al
26
STARS-BNP
20
TIME-CHF
22
BATTLE
21
SCARRED
PRIMA
SIGNAL-HF
Number of patients
Intervention arm
Usual care
33
36
21
20
30
30
110
110
251
248
121
121
174
171
126
124
Follow-up (months)
9.5
3
18
15
18
24
24
9
Mean age (years) ± SD
Intervention arm
Usual care
68
72
64.5 ± 15.2
65.6 ± 13.5
65 ± 5
66 ± 6
76 ± 7
77 ± 8
76
76
71 ± 12
73 ± 12
>18
>18
Mean NYHA functional class
Intervention arm
Usual care
2.3
2.3
2.6
2.4
NA
NA
2.29
2.21
NA
NA
NA
NA
NA
NA
2-4
2-4
Mean LVEF % ± SD
Intervention arm
Usual care
28
26
23.8 ± 8.8
20.9 ± 9.2
Similar in both
groups
31.8 ± 8.4
29.9 ± 7.7
29.8 ± 7.7
29.4 ± 7.9
37
37
31
35
<50
<50
NT-proBNP
BNP
BNP
BNP
NT-proBNP
NT-proBNP
NT-proBNP
NT-proBNP
1,844
2,133
502
702
NA
NA
3,998
4,657
2,012
1,996
2,958
2,932
NT-proBNP
<1700 ng/L
β-blocker
when BNP ,
or when BNP
>10% lower
than previous
value, or BNP
is within ± 10%
previous level
NA
BNP <100 ng/L
NYHA II plus
NT-proBNP
<400 ng/L
(<75 years),
<800 ng/L
(>75 years)
NT-proBNP
<1300 ng/L
Lowest level
achieved 2weeks post HF
BNP or NT-proBNP
Mean baseline
measurement of
BNP or NT-proBNP (ng/L)
Intervention arm
Usual care
Target for BNP guided
therapy
Similar in both
groups
Male >800
Female >1,000
5
BNP to monitor and guide treatment of heart failure patients: August 2012
10
Troughton et
10
al
5
Beck-da25
Silva
Target for usual care
HF score <2 on
Framingham
a
score
Clinical
assessment
Medical adjustment involved
ACE inhibitors,
diuretic,
digoxin,
aldactone,
metolazone
Only β-blocker
Esteban et al
26
Framingham
a
score
STARS-BNP
20
TIME-CHF
22
BATTLE
21
SCARRED
PRIMA
SIGNAL-HF
Physical
examination
NYHA
functional class
<2
HF score <2 on
Framingham
a
score
Clinical
assessment
Clinical
assessment
β-blocker, ACE
inhibitors,
diuretic,
aldactone
β-blocker, ACE
inhibitors, or
ARB, diuretic,
aldactone,
nitrate
β-blocker, ACE
inhibitors,
diuretic,
aldactone,
digoxin,
metolazone
β-blocker, ACE
inhibitors, or
ARB, diuretic,
aldactone,
digoxin
β-blocker, ACE
inhibitors, or
ARB, aldactone
NYHA = New York Heart Association functional class, NA = not available, LVEF = left ventricular ejection fraction, ARB = angiotensin receptor blocker
a
Framingham HF score: one point for each major criteria present, 0.5 point for each minor criteria present. Major criteria: paroxysmal nocturnal dyspnoea; neck vein distention; rales; radiographic
cardiomegaly (increasing heart size on chest radiography); acute pulmonary oedema; S3 gallop; increased central venous pressure (>16 cm H2O at right atrium); hepatojugular reflux; weight loss >4.5
kg in 5 days in response to treatment. Minor criteria: bilateral ankle oedema; nocturnal cough; dyspnoea on ordinary exertion; hepatomegaly; pleural effusion; decrease in vital capacity by one third from
maximum recorded; tachycardia (heart rate>120 beats/min.).
BNP to monitor and guide treatment of heart failure patients: August 2012
11
Cost Impact
A number of cost-effectiveness studies, including the 2007 MSAC report, were
identified that reported on the use of BNP assays to diagnose HF in the emergency
department setting. However, there was a dearth of literature on the use of these
assays to monitor and guide therapy in HF patients. The 2007 MSAC assessment did
report an indicative price of $50.59 for the performance and reporting of a single
test, allowing for a 17 per cent profit and no co-payment. This figure was based on
the purchase of a 100 test kit at a cost of $2,187.50, and a scenario of conducting 10specimens per run, seven days a week. Laboratory costs including salaries, assets and
overheads were included in this estimate.
The current fee for MBS item number 66830 is $58.90.
The current list price for the AxSYM® BNP assay is $3,756.55 for a test kit for 100
specimens. It is estimated that this cost would be reduced to $2,000, and therefore
$20 per sample, when purchased in bulk. However, this price would not take into
account the cost of performing and reporting on the assay (personal communication
Abbott Diagnostics Australia). Roche Diagnostics were contacted regarding the
current cost of the Elecsys® proBNP kit, however no reply was received.
Cardiovascular disease accounts for approximately 11 per cent of Australia’s health
care budget, with chronic heart failure estimated to presently cost one billion
dollars. The current cost of hospitalised patients in acute beds is $1,100/day
compared to $550/day for subacute stays.27 By using BNP measurements to optimise
therapy it is hoped that the number of re-hospitalisations of HF failure patients will
decrease, further reducing overall costs associated with HF.
Only one cost-effectiveness analysis, conducted in Austria, was identified for
inclusion in this Brief.28 Although 278 patients with HF6 were randomised to receive
either usual care, home-based nurse care (HNC) or HNC plus decision-making based
on NT-proBNP levels (BNC), only 190 fulfilled the criteria for a per-protocol analysis.
There was no difference between the treatment groups in age, sex, HF medication
and ventricular function at discharge. HNC and BNC patients participated in two
outpatient clinics 10 days and 2-months post-discharge, in addition to receiving four
home visits by a HF nurse at 1, 3, 6 and 12-months. Patients in the BNC group had a
NT-proBNP test during these visits and those patients with a NT-proBNP level >2200
ng/L -1 received a visit to a HF-outpatient clinic. The price for one determination of
NT-proBNP was €25.85, which currently converts to A$31.74, considerably less than
the $50.59 used in the MSAC report. Re-hospitalisation was estimated to cost €388
(A$476) per bed per night. Home visits by a HF nurse were estimated to cost €80 and
6
NYHA class III or IV, LVEF <40% and cardiothoracic ration >0.5
BNP to monitor and guide treatment of heart failure patients: August 2012
12
a 15 minute outpatient appointment with a cardiologist was estimated to cost
€15.15.
The clinical outcomes for these patients are summarised in Table 5. Death or rehospitalisation was significantly lower in patients who received home-based nurse
care with or without BNP testing, however fewer patients experienced this outcome
in the BNC group (37%, p= 0.001). Mortality rates were also significantly lower in the
HNC and BNC groups compared to usual care.
Table 5
Clinical outcomes for patients included in the economic analysis
Outcome
28
Usual care
(n=47)
Homebased
nurse care
(n=85)
Homebased
nurse care
+ BNC
(n=58)
Death or re-hospitalisation for
HF
66%
53%
37%
Overall
UC vs HNC:
HNC vs BNC:
UC vs BNC:
0.002
0.012
0.311
0.001
Mortality
45%
24%
17%
Overall
UC vs HNC:
HNC vs BNC:
UC vs BNC:
0.004
0.002
0.533
0.017
Re-hospitalised for any cause
83%
75%
65%
Overall
UC vs HNC:
HNC vs BNC:
UC vs BNC:
0.115
0.095
0.698
0.052
Re-hospitalised for HF
60%
41%
25%
Overall
UC vs HNC:
HNC vs BNC:
UC vs BNC:
<0.001
0.014
0.012
<0.001
P-value
Per patient costs for hospitalisation due to worsening heart failure were significantly
less for patients in the BNC group compared to usual care (€2991 vs €7109, p=0.027).
However, it should be noted that the high standard deviation in all care groups
indicates a great deal of variation within the groups (Table 6). Costs in the BNC group
were also significantly less than those for the HNC group (p= 0.033). Although costs
increased marginally in both groups when corrected for death as a competing risk,
costs remained significantly less in the BNC group compared to usual care (€3148 vs
€7893, p= 0.012). Differences between costs in the HNC and BNC groups were also
significant (p=0.016). When the costs for all cause re-hospitalisations per year
survived after discharge were calculated, BNC was found to be more cost-effective
than usual care (€8787 vs €19694, p = 0.015), again with high standard deviations in
all groups indicating a great deal of variation. The cost-effectiveness ratio of HNC and
BNC compared to usual care was €0.83 and €24.85, respectively, indicating that both
care groups cost less and result in longer survival times. In all models HNC was cost
neutral and NT-proBNP testing in addition to HNC was found to be cost-effective and
cheaper than usual care.28 Although this study was limited by the relatively small
BNP to monitor and guide treatment of heart failure patients: August 2012
13
number of patients in each group, it was considered unlikely that the results would
be biased towards the BNC group.
Table 6
Costs for clinical outcomes
28
Costs
Usual care
Home-based
nurse care
Home-based
nurse care +
BNC
Including all-cause re-hospitalisations
€12,450 ±
16,185
€12,391 ±
16,641
€9,674 ±
11,309
Including all-cause re-hospitalisations
correcting for death as a competing risk
€14,737 ±
16,064
€13,828 ±
16,757
€10,235 ±
11,439
Including only hospitalisation due to
worsening HF
€7,109 ±
11,687
€5,225 ± 7,508
€2,991 ± 4,885
Including only hospitalisation due to
worsening HF correcting for death as a
competing risk
€7,893 ±
11,734
€5,740 ± 7,787
€3,148 ± 4,949
Considering all-cause re-hospitalisations
€19,694 ±
26,754
€14,262 ±
25,330
€8,787 ±
14,728
Considering re-hospitalisation due to
congestive HF
€15,151 ±
26,791
€7,084 ±
17,170
€3,978 ±
13,261
Cost-effectiveness
Ethical, Cultural or Religious Considerations
No issues were identified/raised in the sources examined.
Other Issues
The RCT conducted in New Zealand by Lainchbury et al (2009), The BNP Assisted
Treatment to Lessen Serial Cardiac Readmissions and Death, appears to be ongoing.
The 2009 study reported on 364 HF patients randomised to therapy guided by NTproBNP levels, intensive clinical management or usual care. When registered on the
Australian New Zealand Clinical Trials Registry (ACTRN12605000735651) this trial
aimed to recruit 1,000 HF patients.
Summary of Findings
Levels of BNP and NT-proBNP are elevated in heart failure patients, with increasing
levels correlating with an increased severity of symptoms. BNP and NT-proBNP
assays are currently approved by the MBS for the diagnosis of heart failure, however
insufficient evidence was available for the use of BNP to monitor the treatment of
heart failure patients when this indication was assessed by the MSAC in 2007. Since
2007, several medium to large RCTs have been published, with total enrolments
ranging from 220 to 499 heart failure patients. These studies, plus the results of two
studies presented at conferences, were included in a meta-analysis of BNP-guided
treatment of HF patients compared to usual care. All-cause mortality was lower in
patients whose post-discharge HF treatment was guided by the use of BNP
compared to those patients who received usual care (RR= 0.76, p=0.003). A subBNP to monitor and guide treatment of heart failure patients: August 2012
14
group analysis found that all-cause mortality in patients <75 years with HF treatment
guided by BNP testing was lower (RR= 0.52, p=0.005) compared to patients treated
with usual care, a difference that was absent in those aged >75 years (RR = 0.94,
p= 0.70). There was no significant difference between the intervention and usual
care groups for the outcome of all-cause hospitalisation (RR = 0.82, p= 0.12) or for
survival free of any hospitalisation (RR = 1.07, p= 0.58). However, these last three
outcomes were not reported by all studies.
The one cost-effectiveness analysis included for assessment was relatively small but
concluded that BNP-guided treatment of heart failure patients was found to be more
cost-effective than usual care. It is unclear if the results of this Austrian analysis
would be generalisable to Australia or New Zealand, however base costs were
similar, albeit lower, to those used in the Australian health system.
HealthPACT Assessment:
Anecdotal evidence suggests the MBS item number that describes the use of BNP
tests for the diagnosis of heart failure is being used “off-label” to monitor the
treatment of heart failure patients. Since the publication of the 2007 MSAC
assessment a wealth of good quality RCTs have been published that describe the use
of BNP or NT-proBNP assays to monitor therapy in heart failure patients. In addition,
an on-going New Zealand study is currently being conducted that intends to enrol
the largest patient group to date and offers the potential for a cost-effectiveness
analysis being conducted that is relevant to the Australasian health system.
HealthPACT have recommended that jurisdictional data on the use of the BNP MBS
item number be collated and that this information be brought to the attention of the
Medical Benefits Branch with a view that a full health technology assessment be
conducted.
Number of Studies included
All evidence included for assessment in this Technology Brief has been assessed
according to the revised NHMRC levels of evidence. A document summarising these
levels may be accessed via the following link on the HealthPACT web site.
Total number of studies
Total number of Level I intervention studies
1
1: a meta-analysis of 8 RCTs
(level II intervention studies)
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Search Criteria to be used (MeSH Terms)
Biological Markers/blood
BNP to monitor and guide treatment of heart failure patients: August 2012
17
Heart Failure/diagnosis
Heart Failure/drug therapy*
Monitoring, Physiologic
Natriuretic Peptide, Brain/blood*
BNP to monitor and guide treatment of heart failure patients: August 2012
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