“ASSOCIATION OF COPEPTIN AND NTERMINAL PROBNP
CONCENTRATIONS WITH RISK OF
CARDIOVASCULAR DEATH IN OLDER
PATIENTS WITH SYMPTOMS OF
HEART FAILURE”
Alehagen U, Dahlstrom U, Rehfeld JF, Goetze JP.
JAMA. 2011;305(20):2088-2094.
Polly Rimtepathip
Pharm.D. Candidate
September 23, 2011
FUNDING

Grants from the County Council of Ostergotland,
the Swedish Heart and Lung Foundation, and
the University of Linkoping
OBJECTIVE

To evaluate the association of combined plasma
copeptin and N-terminal fragment of the
precursor to B-type natriuretic peptide (NTproBNP) concentrations with mortality in elderly
patients with symptoms of heart failure
BACKGROUND

B-type natriuretic peptide (BNP)



Secreted by the ventricles of the heart in response to
excessive stretching of heart muscle cells or
cardiomyocytes.
co-secreted with N-terminal fragment (NT-proBNP)
which is biologically inactive
NT-proBNP
Precursor of BNP
 Its half-life is longer than the BNP (1-2 hrs vs 20
mins)


Both BNP and NT-proBNP levels in the blood are
used as markers for heart failure (HF)

Both levels increases when HF symptoms worsen and
decreases as heart failure condition is stable
BACKGROUND

Vasopressin
A non-cardiac plasma marker of cardiovascular disease
 Released from the neurohypophysis (posterior pituitary) in
response to changes in plasma osmolality and is involved
in osmoregulation and cardiovascular homeostasis
 The plasma concentration of vasopressin increases in
patients with HF and is associated with left ventricular
dysfunction.


Copeptin
C-terminal fragment of the arginine vasopressin (AVP)
precursor hormone
 circulating copeptin levels reflect the activity of the AVP
system and correlate closely with plasma osmolality

BACKGROUND
Vasopressin is not a useful plasma marker
because it rapidly degrades in the circulation
 Therefore, copeptin, a provasopressin, has
emerged as a promising measurement in place of
vasopressin concentration
 Measurements of copeptin has been mainly
tested in patients with severe infection, and some
reports suggested its possible role in
cardiovascular disease
 As a result, this study was designed to look at the
copeptin’s role in combination with NT-proBNP
concentrations in predicting clinical outcomes of
elderly patients with HF symptoms

STUDY DESIGN



Conducted between January and December of 1996
with follow-up through December 2009 (13-year
follow-up)
1-center, prospective cohort study
Setting


Sample


All elderly patients aged 65-87 years with symptoms
and/or signs of heart failure were evaluated
Sample size


A primary health care center in southeast Sweden
470 patients participated with the mean age of 73 years old
and an equivalent distribution of men and women.
Symptoms and/or signs of HF included shortness of
breath, peripheral edema and/or fatigue.
METHODS

For each patient, a new patient record was
started and clinical examination was performed:
New York Heart Association (NYHA) functional class
 Doppler echocardiography
 Standard blood analyses

HF was diagnosed as a combination of symptoms
and/or signs and an ejection fraction < 40% on
echocardiography.
 Mortality information was obtained from the
Swedish National Board of Health and Welfare,
which registers all deaths of Swedish citizens.

STATISTICAL ANALYSIS
Descriptive data are presented as percentages or
means with standard deviations.
 Analyses were calculated using an unpaired 2sided t test for continuous variables.
2
 The X test was used for discrete variables.
 Evaluation of correlation was analyzed using the
Pearson product-moment correlation coefficient.
 Cox proportional hazard regression analyses
were used to analyze the risk of both all-cause
and cardiovascular mortality during the followup period.

STATISTICAL ANALYSIS

X2 test (chi-square)
Used with discrete data to test the null hypothesis
 A statistical method for determining the approximate
probability of whether the results of an experiment
may arise by chance or not.
 The test is performed by first creating a 2X2
contingency table of the observed disease and test
outcome frequencies.
 Uses – to determine whether the distributions of two
variables are independent of each other and to test a
sample against an expected distribution

MAIN OUTCOME

All-cause mortality and cardiovascular mortality
RESULTS
RESULTS
During the follow-up, there were 226 deaths
(48%) from all causes with 146 cardiovascular
deaths (31%).
 Concentrations of copeptin and NT-proBNP were
associated with long-term all-cause mortality,
both separately and in combination
 Prognostic information obtained by the markers
was greater when both were combined

RESULTS
44 of 52 patients (84.6%) were correctly identified
as high risk in the group with both markers in
the highest quartiles, compared with 99 of 287
patients (34.5%) with all-cause mortality and
concentrations of both markers in the first
quartile.
 36 of 52 patients (69.2%) were correctly identified
as at high risk with both markers in the highest
quartiles, compared with 61 of 287 (21.3%) with
cardiovascular mortality and concentrations of
both markers in the first quartile.

RESULTS

In all-cause mortality, when both markers were
evaluated together, 6.8% more patients were
correctly identified as at risk compared with only
using NT-proBNP concentration over a 13-year
follow-up period


8.4% more were correctly identified in 10 years
follow-up
In cardiovascular mortality over 13 years, 12.3%
more were correctly identified as at risk

19.6% more were correctly identified in 10 years
follow-up.
DISCUSSION
Additive prognostic information was
demonstrated for both all-cause and
cardiovascular mortality.
 Both NT-proBNP and copeptin provided
independent prognostic information.
 Because of the nature of the sample population,
the study more accurately represent the
population with heart failure seen in primary
care.

DISCUSSION
The study can help with the interpretation of
symptoms of heart failure in elderly patients
because they often present with other diseases,
which could make the interpretation difficult.
 The data suggests that vasopressin may be a
potential target for therapeutic intervention.

CONCLUSION

Concentrations of copeptin and NT-proBNP
together can provide a prognostic information in
elder patients with symptoms of heart failure.
Elevated level of copeptin and NT-proBNP were
associated with increased risk of all-cause
mortality.
COMMENT

NT-proBNP was an established marker of heart
failure, but when evaluate the concentration
along with copeptin concentration, the accuracy
level increases.
However, the clinical significance of the outcome
need to be evaluated
 Cost versus benefit analysis of using the two markers
instead of one will be helpful in practice.


The study opens the door to other researches
regarding the roles of copeptin in heart failure
and other diseases other than severe infection.