Download Coronary Heart Disease

Coronary Heart Disease
Evaluation of Multiple Biomarkers of Cardiovascular Stress
for Risk Prediction and Guiding Medical Therapy in
Patients With Stable Coronary Disease
Marc S. Sabatine, MD, MPH; David A. Morrow, MD, MPH; James A. de Lemos, MD;
Torbjorn Omland, MD, PhD; Sarah Sloan, MS; Petr Jarolim, MD, PhD; Scott D. Solomon, MD;
Marc A. Pfeffer, MD, PhD; Eugene Braunwald, MD
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Background—Circulating biomarkers can offer insight into subclinical cardiovascular stress and thus have the potential to
aid in risk stratification and tailoring of therapy.
Methods and Results—We measured plasma levels of 4 cardiovascular biomarkers, midregional pro-atrial natriuretic peptide
(MR-proANP), midregional pro-adrenomedullin (MR-proADM), C-terminal pro-endothelin-1 (CT-proET-1), and copeptin,
in 3717 patients with stable coronary artery disease and preserved left ventricular ejection fraction who were randomized to
trandolapril or placebo as part of the Prevention of Events With Angiotensin Converting Enzyme (PEACE) trial. After
adjustment for clinical cardiovascular risk predictors and left ventricular ejection fraction, elevated levels of MR-proANP,
MR-proADM, and CT-proET-1 were independently associated with the risk of cardiovascular death or heart failure (hazard
ratios per 1-SD increase in log-transformed biomarker levels of 1.97, 1.48, and 1.47, respectively; Pⱕ0.002 for each
biomarker). These 3 biomarkers also significantly improved metrics of discrimination when added to a clinical model.
Trandolapril significantly reduced the risk of cardiovascular death or heart failure in patients who had elevated levels of ⱖ2
biomarkers (hazard ratio, 0.53; 95% confidence interval, 0.36 – 0.80), whereas there was no benefit in patients with elevated
levels of 0 or 1 biomarker (hazard ratio, 1.09; 95% confidence interval, 0.74 –1.59; Pinteraction⫽0.012).
Conclusions—In patients with stable coronary artery disease and preserved left ventricular ejection fraction, our results
suggest that elevated levels of novel biomarkers of cardiovascular stress may help identify patients who are at higher
risk of cardiovascular death and heart failure and may be useful to select patients who derive significant benefit from
angiotensin-converting enzyme inhibitor therapy. (Circulation. 2012;125:233-240.)
Key Words: angiotensin-converting enzyme inhibitors 䡲 biomarkers 䡲 coronary disease
E
levated levels of circulating biomarkers related to cardiac
volume or pressure overload offer insight into subclinical
cardiac stress and thus have the potential to aid in risk
stratification.1 Specifically, elevated levels of B-type natriuretic peptide (BNP; either the hormone or the aminoterminal fragment of the prohormone [NT-proBNP]) have
been shown to be predictive of mortality and/or heart failure
events across a broad range of individuals, ranging from the
general population to patients with overt heart failure.1–7
relation to cardiomyocyte and/or vascular stress offers the
potential for more refined risk assessment. Specifically, atrial
natriuretic peptide (ANP) is a vasodilator and natriuretic that
is synthesized in the myocardium in response to increased
wall tension.8 Adrenomedullin (ADM) is a potent vasodilator
synthesized in the adrenal medulla, vascular endothelial cells,
heart, and elsewhere in response to physical stretch and
specific cytokines, with levels in the heart elevated in the
setting of pressure and volume overload.9,10 Endothelin-1
(ET-1) is a potent vasoconstrictor and profibrotic hormone
that is secreted by vascular endothelial cells, with levels
correlating with shear stress and pulmonary artery pressure.11
Copeptin is a stable peptide derived from the precursor to
Clinical Perspective on p 240
Development of newer assays that target more stable
epitopes of hormones or prohormones that are released in
Received August 24, 2011; accepted December 7, 2011.
From the TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital and Department of Medicine, Harvard Medical School, Boston,
MA (M.S.S., D.A.M., S.S., E.B.); Division of Cardiology, University of Texas Southwestern Medical Center, Dallas (J.A.d.L.); Division of Medicine,
Akershus University Hospital and Center for Heart Failure Research and KG Jebsen Cardiac Research Center, University of Oslo, Oslo, Norway (T.O.);
Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA (P.J.); and Cardiovascular Division, Brigham and
Women’s Hospital, Harvard Medical School, Boston, MA (S.D.S., M.A.P.).
Guest Editor for this article was Gregg C. Fonarow, MD.
The online-only Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.
111.063842/-/DC1.
Correspondence to Marc S. Sabatine, MD, MPH, TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital, 350 Longwood Ave,
Boston, MA 02115. E-mail [email protected]
© 2011 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org
DOI: 10.1161/CIRCULATIONAHA.111.063842
233
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January 17, 2012
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arginine vasopressin, a vasoconstrictor that is secreted from
the posterior pituitary in response not only to osmotic stimuli
but also to hemodynamic changes detected by cardiac and
vascular baroreceptors.12 Higher levels of these biomarkers
have been associated with an increased risk of death and/or
heart failure events in patients with established heart failure.13–16 The availability of an assay panel for these 4
biomarkers of cardiovascular stress that have shown promise
in patients with established heart failure created the opportunity to investigate their utility in a broader population.
Angiotensin-converting enzyme (ACE) inhibitors substantially reduce the risk of death and heart failure events in patients
with heart failure, with the greatest benefit in those patients with
the most clinically severe heart failure.17 Among patients with
acute myocardial infarction (MI), the benefit of ACE inhibitors
is greatest in those with high-risk clinical features such as
anterior MI or depressed left ventricular systolic function.18 In
contrast, the role of ACE inhibitors in lower-risk patients with
stable coronary artery disease (CAD) without heart failure is less
clear.19 –21 We explored the hypotheses that in such patients,
elevated levels of midregional (MR) pro-ANP, MR-proADM,
C-terminal proET-1 (CT-proET-1), and copeptin would offer
prognostic value for cardiovascular death and heart failure
independently of clinical risk factors and would identify patients
who derive greater clinical benefit from the use of an ACE
inhibitor. We tested these hypotheses by measuring plasma
levels of these novel biomarkers of cardiovascular stress in 3717
patients with stable CAD and preserved left ventricular ejection
fraction (LVEF) who were randomized to trandolapril or placebo as part of the Prevention of Events With Angiotensin
Converting Enzyme (PEACE) trial.
Methods
Patient Population
This study involved 3717 patients with documented stable CAD who
had been enrolled in the PEACE trial (www.ClinicalTrials.gov;
unique identifier, NCT00000558) and provided a sample of blood at
the time of enrollment. The design and main outcomes of the PEACE
trial have been published previously,21 and salient features are
detailed in the Methods section and Table I in the online-only Data
Supplement. In brief, subjects were free of heart failure at baseline,
and none had been hospitalized with an acute coronary syndrome or
had undergone coronary revascularization within the 3 months
preceding trial entry. Both the parent clinical trial and this substudy
were approved by the relevant institutional review boards, and
informed consent was obtained from all patients.
Biomarker Analyses
Baseline plasma levels of MR-proANP,22 MR-proADM,23 CTproET-1,24 and copeptin25 (assays from B.R.A.H.M.S. GmbH, Henningsdorf, Germany) were determined in the Thrombolysis in Myocardial Infarction (TIMI) Clinical Trials Laboratory (Boston, MA) as
detailed in the Methods section and Table II in the online-only Data
Supplement. Baseline levels of NT-proBNP and cardiac troponin T
(cTnT) measured with a highly sensitive assay had been determined
in this population, as previously published and summarized in the
Methods section in the online-only Data Supplement.6,26 All testing
was performed by personnel blinded to clinical outcomes and
treatment allocation.
Outcomes
On the basis of prior data regarding the predictive ability of
biomarkers of cardiac stress,6 the primary outcome in this analysis
was the composite of cardiovascular death or hospitalization for
heart failure. Additionally, we explored other major adverse cardiovascular events that had been recorded in patients in the trial,
including all-cause death, acute MI, acute stroke, and coronary
revascularization (percutaneous or surgical). Event adjudication is
detailed in the Methods section in the online-only Data Supplement.
All clinical events were classified before biomarkers were measured.
Statistical Analyses
Baseline characteristics are reported as mean⫾SD for normally distributed continuous variables and as counts and percentages for categorical
variables. Wilcoxon rank-sum and ␹2 tests for trend were used to test for
differences in continuous and categorical baseline characteristics between quartiles of biomarkers. The Spearman correlation was used to
calculate the association between different biomarkers and categorized
based on standard cut points.27 The cumulative incidences of clinical
outcomes across quartiles of each biomarker were compared by use of
a log-rank test. Cox proportional-hazards models were used to examine
the association between biomarker levels and outcome data. In these
models, biomarker levels were examined both as a continuous variable
(after natural logarithmic transformation) and as a categorical variable
by quartiles. Associations were adjusted for age, sex, weight, history of
hypertension, history of diabetes mellitus, current tobacco use, prior MI,
prior percutaneous coronary intervention or coronary artery bypass
grafting, systolic blood pressure, estimated glomerular filtration rate,
ratio of apolipoprotein B to apolipoprotein A, LVEF, aspirin use,
␤-blocker use, and lipid-lowering medication use. Starting with a model
containing the aforementioned clinical covariates, a forward selection
algorithm (P⬍0.05 to enter the model) was used to select among the 4
novel biomarkers, as well as NT-proBNP and cTnT. The incremental
performance of the biomarkers in addition to clinical predictors was
further evaluated by calculating changes in the C statistic, integrated
discrimination improvement, and category-free net reclassification improvement metrics (see the Methods section in the online-only Data
Supplement for further details).28 –30
To examine for heterogeneity in the effect of trandolapril on the risk
of cardiovascular death or heart failure, hazard ratios (HRs) were
calculated in patients who were and were not in the highest-risk category
as defined by being in the top quartile of a biomarker level. To test for
statistically significant effect modification, a Cox proportional hazards
model was created that included a term for trandolapril, a term for
biomarker risk category, and an interaction term.
A value of P⬍0.05 was considered to indicate statistical significance,
and all tests were 2 sided. No adjustment for multiple comparisons was
performed. Although based on previous work with these biomarkers in
other populations, all of the analyses we have performed in this
biomarker substudy are inherently exploratory. Analyses were performed with STATA/IC (version 10.1, STATA Corp, College Station,
TX) and R (version 2.12.1).
Results
Baseline Characteristics of the Patients and
Biomarker Levels
Baseline measurements of the 4 novel biomarkers were available
for 3717 patients from the PEACE trial. The clinical characteristics of the patients are given in Table 1. By design, all patients
had stable CAD, and LVEF was preserved at a mean⫾SD value
of 58.7⫾9.6%. Median levels of MR-proANP, MR-proADM,
CT-proET-1, and copeptin at baseline in patients in the PEACE
trial were 90.45 pmol/L (25th–75th percentile, 63.68 –128.3
pmol/L), 0.53 nmol/L (25th–75th percentile, 0.45– 0.64 nmol/L),
47.82 pmol/L (25th–75th percentile, 39.04 –57.02 pmol/L), and
6.47 pmol/L (25th–75th percentile, 0 –10.67 pmol/L), respectively. The levels tended to be higher than those seen in healthy
populations, but with the exception of MR-proADM, the majority of values were lower than the 97.5th percentile reported in
healthy populations and lower than the values in patients with
Sabatine et al
Table 1.
Biomarkers of Cardiovascular Stress in Stable CAD
Baseline Characteristics of Patients
Baseline Characteristic
All
Placebo
Trandolapril
3717
1868
1849
Age, y
64.1⫾8.2
64.1⫾8.2
64.2⫾8.1
Female sex, n (%)
701 (18.9)
334 (17.9)
367 (19.9)
Weight, kg
83.9⫾15.7
83.7⫾15.7
84.2⫾15.6
1658 (44.6)
835 (44.7)
823 (44.5)
Patients, n
Hypertension, n (%)
Diabetes mellitus, n (%)
602 (16.2)
294 (15.7)
308 (16.7)
Current smoker, n (%)
564 (15.2)
290 (15.5)
274 (14.8)
Prior MI, n (%)
2087 (56.2)
1076 (57.6)
1011 (54.7)
Prior PCI or CABG, n (%)
2697 (72.6)
1367 (73.2)
1330 (72.0)
Aspirin use, n (%)
3389 (91.2)
1721 (92.2)
1668 (90.3)
␤-blocker use, n (%)
2303 (62.0)
1156 (61.9)
1147 (62.1)
Lipid-lowering therapy use, n (%)
2667 (71.8)
1334 (71.5)
1333 (72.2)
SBP, mm Hg
133.4⫾16.8 133.4⫾16.8 133.3⫾16.8
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DBP, mm Hg
78.1⫾10.0
78.2⫾10.2
78.0⫾9.8
GFR, mL 䡠 min⫺1 䡠 1.73 m⫺2
77.9⫾19.4
78.3⫾19.4
77.6⫾19.3
ApoB, mg/dL
107.2⫾23.1 107.6⫾22.9 106.8⫾23.2
ApoA, mg/dL
138.2⫾24.6 138.6⫾24.5 137.8⫾24.7
LVEF, %
58.7⫾9.6
58.7⫾9.6
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of MR-proANP and NT-proBNP (r⫽0.76), but correlations of
NT-proBNP and cTnT with other markers were weak (rⱕ0.38;
Table VII in the online-only Data Supplement).
Clinical Outcomes
Among patients allocated to the placebo arm of the PEACE trial,
higher baseline levels of each of the 4 novel biomarker of
cardiovascular stress were strongly associated with the subsequent risk of cardiovascular death or heart failure (the composite
of which occurred in 114 patients), with up to approximately a
doubling of the risk per each 1-SD increase in log-transformed
biomarker levels (Pⱕ0.002 for each biomarker; Table 2). Risk
increased across quartiles, especially the fourth quartile (Figure
1). Similar associations were seen between biomarker levels and
the risk of cardiovascular death (which occurred in 67 patients)
and of heart failure individually (which occurred in 56 patients;
Table VIII in the online-only Data Supplement).
After adjustment for traditional clinical risk predictors, estimated glomerular filtration rate, and LVEF (see Methods for a
detailed list of covariates), elevated levels of MR-proANP,
MR-proADM, and CT-proET-1 remained significantly associated with an increased risk of cardiovascular death or heart
failure, ranging from 47% higher risk to a near doubling of the
risk per each 1-SD increase in log-transformed biomarker levels
(Pⱕ0.002 for each biomarker); in terms of quartile analysis, the
risk was most pronounced for those patients in the top quartile,
who had almost 3 times to ⬎5 times the risk seen for patients in
the lowest quartile. In contrast, after multivariable adjustment,
the association with copeptin was no longer significant (Table
3). As was the case for the unadjusted analyses, similar associations were seen between biomarker levels and the risk of
cardiovascular death and of heart failure individually (Table
VIII in the online-only Data Supplement). Compared with
cardiovascular death, the associations with the less cardiovascular-specific end point of all-cause death were significant
but weaker (Table IX in the online-only Data Supplement).
As expected on the basis of prior work,6,26 there were
nonsignificant adjusted associations between levels of novel
biomarkers of cardiovascular stress and the risk of acute MI,
stroke, or coronary revascularization, with the exception of
MR-proANP and stroke (P⫽0.043; Table IX in the onlineonly Data Supplement).
58.8⫾9.7
MI indicates myocardial infarction; PCI, percutaneous coronary intervention;
CABG, coronary artery bypass grafting; SBP, systolic blood pressure; DBP,
diastolic blood pressure; GFR, glomerular filtration rate; ApoB, apolipoprotein B;
ApoA, apolipoprotein A; and LVEF, left ventricular ejection fraction. Data are
presented as mean⫾SD for normally distributed continuous variables and n (%)
for dichotomous variables.
overt heart failure (Table II in the online-only Data Supplement).
Characteristics of patients according to quartiles of biomarker
levels are shown in Tables III through VI in the online-only Data
Supplement. In general, higher levels of biomarkers of cardiovascular stress were positively associated with greater age and
prevalence of hypertension and lower estimated glomerular
filtration rate. LVEF was inversely associated with MR-proANP
and copeptin levels but differed by only 2.0 and 1.0 absolute
percentage points between the top and bottom quartiles for the 2
biomarkers, respectively. Among the novel biomarkers, the only
moderately strong correlation was between MR-proADM and
CT-proET-1 (r⫽0.63); the others were moderate to low
(rⱕ0.44; Table VII in the online-only Data Supplement). As
expected, there was a strong positive correlation between levels
Table 2. Association of Biomarker Levels and Clinical Outcomes in the Placebo Arm
Risk for CV Death or Heart Failure
Biomarker
MR-proANP
HR (95% CI) per 1-SD
Increase in Log-Transformed
Biomarker Values
P
1
2
3
4
Multiple Partial
Trend
2.25 (1.89 –2.42)
⬍0.001
Referent
1.92 (0.85– 4.30)
3.10 (1.46 – 6.59)
7.30 (3.62–14.70)
⬍0.0001
⬍0.0001
HR (95% CI) Across Quartiles
P
MR-proADM
1.69 (1.52–1.88)
⬍0.001
Referent
2.15 (0.88–5.28)
3.65 (1.58–8.45)
10.25 (4.71–22.33)
⬍0.0001
⬍0.0001
CT-proET-1
1.96 (1.57–2.44)
⬍0.001
Referent
2.25 (1.14–4.45)
1.42 (0.68–2.98)
5.07 (2.72–9.44)
⬍0.0001
⬍0.0001
Copeptin
1.30 (1.10–1.55)
0.002
Referent
0.88 (0.43–1.79)
1.23 (0.74–2.05)
2.09 (1.32–3.28)
0.0072
0.0013
CV indicates cardiovascular; HR, hazard ratio; CI, confidence interval; MR-proANP, midregional pro-atrial natriuretic peptide; MR-proADM, midregional
pro-adrenomedullin; and CT-proET-1, C-terminal pro-endothelin-1. A total of 114 of the 1868 patients allocated to placebo experienced CV death or heart failure. Each
biomarker was analyzed separately. In quartile analyses, “multiple partial” refers to a 3-df test for the addition of all quartiles and “trend” refers to a 1-df test for
linear trend across quartiles.
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Figure 1. Cumulative incidence curves for the composite of cardiovascular death or heart failure among patients in the placebo arm of
the Prevention of Events With Angiotensin Converting Enzyme (PEACE) trial (n⫽1868) categorized by quartiles of midregional pro-atrial
natriuretic peptide (MR-proANP), midregional pro-adrenomedullin (MR-proADM), C-terminal pro-endothelin-1 (CT-proET-1), or copeptin.
P values are for log-rank test for trend across quartiles.
unbiased forward selection algorithm to create a multimarker
model. The only 2 biomarkers to enter and remain in a model
already containing clinical covariates were MR-proANP (adjusted HR, 1.79; 95% confidence interval [CI], 1.41–2.26;
P⬍0.001) and MR-proADM (adjusted HR, 1.27; 95% CI,
1.07–1.51; P⫽0.007).
The addition of MR-proANP, MR-proADM, and CTproET-1 individually to the clinical model significantly improved metrics of discrimination (Table 4). In contrast, the
addition of copeptin did not improve these metrics. The addition
We have previously measured NT-proBNP and cTnT in this
population, and the association of those biomarkers with cardiovascular death or heart failure in a model adjusted for the
aforementioned clinical covariates is shown in Table X in the
online-only Data Supplement. Ranking each biomarker individually on the basis of the magnitude of risk (HR) per 1 SD gives
the following order: MR-proANP (1.97), NT-proBNP (1.73),
MR-proADM (1.48), CT-proET-1 (1.47), and cTnT (1.37).
Given the correlation between the biomarkers and that none is
established for routine use in this population, we used an
Table 3. Multivariable-Adjusted Association of Biomarker Levels and Clinical Outcomes in the Placebo Arm Adjusted for Clinical Factors
Adjusted Risk for CV Death or Heart Failure
HR (95% CI) per 1-SD
Increase in Log-Transformed
Biomarker Values
P
1
2
3
4
Multiple Partial
Trend
1.97 (1.58 –2.46)
⬍0.001
Referent
1.60 (0.70 –3.66)
2.72 (1.24 –5.96)
4.35 (1.96 –9.62)
⬍0.0001
⬍0.0001
MR-proADM
1.48 (1.27–1.73)
⬍0.001
Referent
1.90 (0.77–4.69)
2.45 (1.03–5.82)
5.51 (2.38–12.75)
⬍0.0001
⬍0.0001
CT-proET-1
1.47 (1.15–1.88)
0.002
Referent
2.03 (1.03–4.04)
0.99 (0.46–2.11)
2.73 (1.41–5.27)
⬍0.001
0.01
Copeptin
1.10 (0.91–1.33)
0.32
Referent
0.77 (0.37–1.57)
1.11 (0.66–1.86)
1.41 (0.87–2.28)
0.30
0.11
Biomarker
MR-proANP
HR (95% CI) Across Quartiles
P
CV indicates cardiovascular; HR, hazard ratio; CI, confidence interval; MR-proANP, midregional pro-atrial natriuretic peptide; MR-proADM, midregional
pro-adrenomedullin; and CT-proET-1, C-terminal pro-endothelin-1. Covariates in the model include standard clinical factors: age, sex, weight, history of hypertension,
history of diabetes mellitus, current tobacco use, prior myocardial infarction, prior percutaneous coronary intervention or coronary artery bypass graft surgery, systolic
blood pressure, estimated glomerular filtration rate, ratio of apolipoprotein B to A, left ventricular ejection fraction, aspirin use, ␤-blocker use, and lipid-lowering
medication use. Each biomarker was analyzed separately in the placebo arm. In quartile analyses, “multiple partial” refers to a 3-df test for the addition of all quartiles
and “trend” refers to a 1-df test for linear trend across quartiles.
Sabatine et al
Biomarkers of Cardiovascular Stress in Stable CAD
Table 4. Impact of Biomarker Levels and Metrics of
Discrimination and Reclassification in the Placebo Arm
C Statistic
Integrated
Discrimination
Index
Net
Reclassification
Improvement
Model
Value
P
Value, %
P
Value
P
Clinical model
alone
0.768
N/A
N/A
N/A
N/A
N/A
⬍0.0001 0.412 ⬍0.0001
Clinical model⫹ 0.804 0.0018
MR-proANP
3.8
Clinical model⫹ 0.788 0.0064
MR-proADM
1.9
0.0027 0.362
0.0003
Clinical model⫹ 0.779 0.23
CT-proET-1
1.2
0.047
0.205
0.039
Clinical model⫹ 0.769 0.85
copeptin
0.2
0.14
0.061
0.54
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MR-proANP indicates midregional pro-atrial natriuretic peptide; MR-proADM,
midregional pro-adrenomedullin; and CT-proET-1, C-terminal pro-endothelin-1.
Terms in the clinical model include age, sex, weight, history of hypertension, history
of diabetes mellitus, current tobacco use, prior myocardial infarction, prior
percutaneous coronary intervention or coronary artery bypass graft surgery, systolic
blood pressure, estimated glomerular filtration rate, ratio of apolipoprotein B to A,
left ventricular ejection fraction, aspirin use, ␤-blocker use, and lipid-lowering
medication use. Each biomarker was analyzed separately in the placebo arm. P
values are for comparison with clinical model alone.
of all 3 biomarkers to the clinical model improved the C statistic
from 0.768 to 0.809 and yielded an integrated discrimination
improvement of 4.6% and an net reclassification improvement
of 0.435 (all Pⱕ0.0005). Adding MR-proANP, MR-proADM,
237
and CT-proET-1 uniformly and significantly improved the C
statistic of multivariable models already containing clinical
covariates, regardless of whether NT-proBNP, cTnT, or both
were also in the model; conversely, adding NT-proBNP and
cTnT to a model containing clinical covariates as well as
MR-proANP, MR-proADM, and CT-proET-1 did not improve
the C statistic (Table XI in the online-only Data Supplement).
Interaction With Trandolapril Therapy
In the overall biomarker cohort, treatment with trandolapril
resulted in an HR of 0.80 (95% CI, 0.61–1.05) for cardiovascular
death or heart failure. Notably, however, among patients having
an MR-proANP, MR-proADM, or CT-proET-1 level in the top
quartile and thus at the highest risk of cardiovascular death or
heart failure based on these biomarkers, trandolapril significantly reduced the risk of cardiovascular death or heart failure by
34% to 44%, whereas no benefit was observed among those with
lower levels (Figure 2A). In contrast, there was no significant
benefit from treatment with trandolapril among patients in the
highest quartiles of either NT-proBNP or cTnT (Figure I in the
online-only Data Supplement).
A gradient of benefit (Pinteraction⫽0.016) with trandolapril
therapy was observed in patients categorized according to
whether they had elevated levels of 0 (n⫽2037), 1 (n⫽891), 2
(n⫽472), or all 3 (n⫽317) novel biomarkers that we found to be
associated with cardiovascular death or heart failure in adjusted
analyses (Figure 2B). When the results were dichotomized,
among the 2928 patients (79% of the biomarker cohort) with ⱕ1
elevated biomarker, there was no benefit of trandolapril therapy
on the risk of cardiovascular death or heart failure (HR, 1.09;
Figure 2. Benefit of trandolapril on the risk of the composite of cardiovascular (CV) death or heart failure in 3717 patients from the Prevention of Events With Angiotensin Converting Enzyme (PEACE) trial categorized according to their levels of biomarkers of cardiovascular stress. A, Patients are categorized according to whether their level of each biomarker of cardiovascular stress was in the top
quartile (quartile 4) or not (quartiles 1–3). The P values for interaction were 0.16, 0.02, 0.09, and 0.72 for midregional pro-atrial natriuretic peptide (MR-proANP), midregional pro-adrenomedullin (MR-proADM), C-terminal pro-endothelin-1 (CT-proET-1), and copeptin,
respectively. B, Patients are categorized by the number of biomarkers (MR-proANP, MR-proADM, and CT-proET-1) in the top quartile;
the P value for interaction is 0.016. In A and B, the diamonds indicate the effect in the entire biomarker cohort, with the center indicating the point estimate and the left and right ends indicating the 95% confidence interval (CI). The squares and circles indicate the point
estimate, and the horizontal lines indicate the 95% CIs for the effect in each subgroup. HR indicates hazard ratio.
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January 17, 2012
Figure 3. Cumulative incidence curves for
the composite of cardiovascular death or
heart failure in 3717 patients from the Prevention of Events with Angiotensin Converting Enzyme (PEACE) trial categorized by
whether they had ⱕ1 elevated biomarkers
(solid lines; red indicates 1487 patients
treated with placebo; blue, 1441 patients
treated with trandolapril) or ⱖ2 elevated
biomarkers (dashed lines; red indicates 381
patients treated with placebo; blue, 408
patients treated with trandolapril). HR indicates hazard ratio; CI, confidence interval.
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
95% CI, 0.74 –1.59), whereas among the 789 patients (21% of
the biomarker cohort) with ⱖ2 elevated biomarkers, trandolapril
significantly reduced the rate of cardiovascular death or
heart failure (HR, 0.53; 95% CI, 0.36 – 0.80; P⫽0.002,
Pinteraction⫽0.012; Figure 3). The absolute risk reduction over 6
years in this latter group was 7.5%; thus, in this subset, 14 patients
would need to be treated with trandolapril for 6 years to prevent a
cardiovascular death or hospitalization for heart failure.
Discussion
In an exploratory analysis among a large cohort of patients
with stable CAD and preserved LVEF, we have demonstrated
that elevated levels of 3 novel biomarkers of cardiovascular
stress are independently associated with the subsequent risk
of cardiovascular death and heart failure. Specifically, MRproANP, MR-proADM, and CT-proET-1 were associated
with cardiovascular death or heart failure independently of
clinical factors, renal function, and LVEF, ranging from 47%
higher risk to a near doubling of the risk per each 1-SD
increase in log-transformed biomarker levels and almost 3
times to ⬎5 times the risk for patients in the highest
compared with the lowest quartile. In contrast, a fourth
biomarker, copeptin, was not independently associated with
the risk of cardiovascular events. Moreover, and in contrast to
previous results with other biomarkers, including NTproBNP and cTnT,6,26,31 elevated levels of these 3 biomarkers
identified patients in whom, despite appearing to be at low
risk clinically, therapy with an ACE inhibitor resulted in a
significant reduction in the risk of cardiovascular death or
heart failure.
We used assays for the prohormones ANP, ADM, and ET-1
because the prohormones are released in an equimolar ratio to
the vasoactive hormones but have a longer half-life. When
possible, we also used assays for a midregional fragment
because these fragments are more stable in vivo and ex vivo than
the amino- or carboxy-terminal part of the prohormone, thereby
minimizing the risk of underestimation of levels as a result of
early degradation of crucial epitopes at the extreme ends of the
molecule.32 In studies of patients with established heart failure,
elevated levels of MR-proANP, MR-proADM, and CT-proET-1
have been shown to be associated with mortality independently
of clinical variables, and the biomarkers have displayed prognostic and discriminatory value that has compared favorably
with BNP and/or NT-proBNP.13–15
Concordant with those observations, in our data set, we found
that during the creation of a multimarker model adjusted for
clinical factors, MR-proANP and MR-proADM proved to be the
strongest 2 biomarkers, superior to NT-proBNP and cTnT
measured with a highly sensitive assay. Because this was a
clinical rather than a mechanistic study, we can only speculate as
to the reasons for the superior performance, which could be
related to subtle differences in the respective pathobiology
underlying elevation of each of the biomarkers or could stem
from more favorable analytic properties that translate into a
better reflection of subclinical cardiovascular pathology. Regardless, our data are supported by and extend previous findings
regarding these biomarkers and atherosclerosis reported by
Schnabel and colleagues7 in several ways, including studying
patients who were free of heart failure at baseline and whose
LVEF was known and incorporated into all multivariable models, using patients enrolled from a much broader number of
clinical centers, and examining the specific clinical events that
biomarkers of cardiac stress are best suited to predict, namely
cardiovascular death and heart failure, rather than a composite of
death or MI.
Critically, whereas other biomarker analyses have been embedded in observational cohorts, we had the benefit of studying
these biomarkers in a randomized clinical trial, allowing us to
examine the interaction between baseline biomarker levels and
the efficacy of the randomized therapy without concern for the
inherent bias in examining nonrandomly allocated therapies.
Using a panel of these novel biomarkers of cardiovascular stress,
we were able to identify approximately one fifth of enrolled
patients with stable CAD in whom ACE inhibitor therapy nearly
halved the risk of cardiovascular death or heart failure. Our
findings are conceptually analogous to the results of Richards
and colleagues,33,34 who showed that elevated levels of biomarkers of cardiovascular stress identified patients with ischemic left
ventricular dysfunction who benefited from ␤-blockade.
Current practice guidelines for the management of patients
with stable CAD recommend ACE inhibitor therapy in those
patients with an LVEF ⬍40%; in addition, in part on the basis of
data from the Heart Outcomes Prevention Evaluation (HOPE)
trial, ACE inhibitors are recommended for patients who are
relatively high risk and/or have another compelling clinical
indication (eg, hypertension, diabetes mellitus, or chronic kidney
disease).35 In contrast, for lower-risk patients like those in the
PEACE trial, in which the event rate in the placebo arm was
lower than the event rate in the ACE inhibitor arm from the
HOPE trial, the guidelines note that it is reasonable but not
recommended to use ACE inhibitors when cardiovascular risk
factors are well controlled and revascularization has been performed. Our data now support the hypothesis that within this
very large population of patients who appear to be of lower risk
Sabatine et al
Biomarkers of Cardiovascular Stress in Stable CAD
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
clinically, biomarkers of cardiovascular stress levels may be
useful to help guide such decision making. Although additional
prospective analyses will need to be done if these biomarkers
become available for routine clinical use in the United States,
targeting long-term drug therapy based on a panel of biomarkers
should be cost effective.
Several potential limitations of our study deserve consideration. The PEACE clinical trial population, which was predominantly a white, male population ⬎50 years of age, is not
representative of the general population. However, the clinical
and laboratory characteristics of patients in this study are typical
of patients with stable coronary disease, and a high proportion of
patients were treated with ␤-blockers and lipid-lowering therapy.
Blood samples were obtained from only a subgroup of the
participants in the overall PEACE trial, but there were no
clinically relevant differences between patients who did and did
not participate in the biomarker substudy. Banked biosamples
were used, but any sample degradation should be random with
respect to cardiovascular outcomes, and thus any resultant
misclassification should only bias toward the null hypothesis.
The formation of the multimarker score for interaction with
therapy should be considered exploratory, and the optimal
combination of biomarkers and their cut points merits validation
in additional populations. Heart failure events were not a
component of the prespecified primary outcome in the original
trial design but are a well-established outcome predicted by
biomarkers of cardiac stress and prevented by ACE inhibitors in
other populations.6,19,20,26
Conclusion
In apparently low-risk patients with stable CAD and preserved LVEF, elevated levels of novel biomarkers reflecting
cardiovascular stress may be useful both to identify patients
who are at higher risk of cardiovascular death and heart
failure and to select patients who derive a significant benefit
from ACE inhibitor therapy.
Sources of Funding
The PEACE trial was supported by a contract from the National
Heart, Lung, and Blood Institute (NHLBI; N01 HC65149) and by
Knoll Pharmaceuticals and Abbott Laboratories, which also provided
the study medication. Dr Sabatine was supported in part by grant
R01 HL094390 from the NHLBI. Reagent for measurement of
MR-proANP, MR-proADM, CT-proET-1, and copeptin were provided by B.R.A.H.M.S. GmbH (Henningsdorf, Germany). The
NHLBI, Knoll Pharmaceuticals, Abbott Laboratories, and
B.R.A.H.M.S. GmbH had no role in the design and conduct of the
study; collection, management, analysis, and interpretation of the
data; or preparation, review, or approval of the manuscript.
Disclosures
Drs Sabatine, Morrow, and Braunwald and S. Sloan are members of the
TIMI Study Group, which has received research grant support from
Accumetrics, Amgen, AstraZeneca, Beckman Coulter, BG Medicine,
B.R.A.H.M.S. GmbH, Bristol-Myers Squibb, CV Therapeutics, Daiichi
Sankyo Co Ltd, diaDexus, Eli Lilly and Co, Genentech, GlaxoSmithKline, Integrated Therapeutics, Johnson & Johnson, Merck and Co,
Nanosphere, Novartis Pharmaceuticals, Nuvelo, Ortho-Clinical Diagnostics, Pfizer, Roche Diagnostics, Sanofi-aventis, Siemens, and Singulex. Dr Sabatine reports receiving honoraria for educational presentations from Bristol-Myers Squibb and diaDexus, as well as
remuneration for consulting from AstraZeneca, Bristol-Myers Squibb/
Sanofi-aventis Joint Venture, Daiichi-Sankyo/Lilly Partnership, Sanofi-
239
aventis, and Singulex. Dr Morrow reports receiving honoraria for
educational presentations from Eli Lilly; remuneration for consulting
from Beckman-Coulter, Boehringer Ingelheim, Cardiokinetix, Critical
Diagnostics, Gilead, Instrumentation Laboratory, Ikaria, Menarini,
Merck, OrthoClinical Diagnostics, Servier, Roche Diagnostics, and
Siemens; and remuneration from AstraZeneca for adjudication as a
member of a Clinical Events Committee. Dr de Lemos reports receiving
grant support from Roche and Alere, Inc (formerly Biosite) and
consulting income from Alere, Johnson & Johnson Roche Diagnostics,
and Tethys Biomedical. Dr Omland reports receiving speakers’ honoraria from Roche Diagnostics and Abbott Laboratories. Dr Jarolim
reports receiving research support from Amgen, Beckman-Coulter,
Ortho Clinical Diagnostics, Roche Diagnostics, and Siemens Healthcare
Diagnostics; honoraria for educational presentations from Ortho Clinical
Diagnostics; and consulting fees from T2 Biosystems. Dr Pfeffer reports
receiving grant support from Amgen, Novartis, and Sanofi-aventis, as
well as consulting fees from Amgen, Anthera, Boehringer Ingelheim,
Boston Scientific, Bristol-Myers Squibb, Cerenis, Eleven Biotherapeutics, GlaxoSmithKline, Hamilton Health Sciences, Karo Bio, Novartis,
Roche, Salutria, Sanofi Aventis, Servier, and University of Oxford. Dr
Pfeffer is a coinventor on a patent that Brigham and Women’s Hospital
has for the use of inhibitors of the renin-angiotensin system in selected
survivors of MI. His share of the licensing agreements with Novartis and
Boehringer, which are irrevocably transferred to charity, are not linked
to sales. Dr Braunwald reports receiving remuneration for symposia
and/or consulting from Amorcyte, CardioRentis, CVRx, Daiichi Sankyo, Eli Lilly, Genzyme, Medicines Co, and Merck & Co. The other
authors report no conflicts.
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CLINICAL PERSPECTIVE
The benefit of angiotensin-converting enzyme inhibitors in low-risk patients with stable coronary artery disease without heart
failure remains controversial, and current practice guidelines note that it is reasonable but not recommended to use
angiotensin-converting enzyme inhibitors when cardiovascular risk factors are well controlled and revascularization has been
performed. We now demonstrate that elevated levels of 3 novel biomarkers of cardiovascular stress, midregional pro-atrial
natriuretic peptide, midregional pro-adrenomedullin, and C-terminal pro-endothelin-1, are associated with the subsequent risk of
cardiovascular death and heart failure independently of clinical factors (adjusted hazard ratios per 1-SD increase of 1.97, 1.48,
and 1.47, respectively; Pⱕ0.002 for each biomarker). Furthermore, elevated levels of these biomarkers identified patients in
whom therapy with an angiotensin-converting enzyme inhibitor resulted in a significant reduction in the risk of cardiovascular
death or heart failure. Specifically, trandolapril significantly reduced the risk of cardiovascular death or heart failure in patients
who had elevated levels of ⱖ2 biomarkers (hazard ratio, 0.53; 95% confidence interval, 0.36 – 0.80), whereas there was no benefit
in patients with elevated levels of 0 or 1 biomarker (hazard ratio, 1.09; 95% confidence interval, 0.74 –1.59; Pinteraction⫽0.012).
Thus, in patients with stable coronary artery disease and preserved left ventricular ejection fraction, elevated levels of novel
biomarkers of cardiovascular stress identify patients who are at higher risk of cardiovascular death and heart failure and may be
useful to select patients who derive significant benefit from angiotensin-converting enzyme inhibitor therapy.
Evaluation of Multiple Biomarkers of Cardiovascular Stress for Risk Prediction and
Guiding Medical Therapy in Patients With Stable Coronary Disease
Marc S. Sabatine, David A. Morrow, James A. de Lemos, Torbjorn Omland, Sarah Sloan, Petr
Jarolim, Scott D. Solomon, Marc A. Pfeffer and Eugene Braunwald
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
Circulation. 2012;125:233-240; originally published online December 16, 2011;
doi: 10.1161/CIRCULATIONAHA.111.063842
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2011 American Heart Association, Inc. All rights reserved.
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Sabatine: Biomarkers of Cardiovascular Stress in Stable CAD
SUPPLEMENTAL MATERIAL
1
Sabatine: Biomarkers of Cardiovascular Stress in Stable CAD
Supplemental Methods
Patient population
In the overall PEACE trial, a total of 8290 patients with documented stable coronary artery disease and
preserved left ventricular ejection fraction were randomized at 187 clinical centers in the United States, Canada,
and Europe to trandolapril or placebo from November 1996 through June 2000. Subjects were followed for a
median of 4.8 years. As part of the study protocol, a sample of venous blood was obtained in EDTA-treated
tubes at the time of enrollment. Participation in the biomarker substudy was at the discretion of each clinical
center and there were no clinically relevant differences between patients included in the substudy and the
overall trial population (Supplemental Table 1). The plasma component was aspirated and frozen at -20 oC at
individual centers. Within 3 months after collection, plasma samples were shipped on dry ice to a central
laboratory for storage at -70 oC or colder until thawed for determination of biomarkers.
2
Sabatine: Biomarkers of Cardiovascular Stress in Stable CAD
Biomarker analyses
Levels of MR-proANP, MR-proADM, CT-proET-1, and copeptin were determined using the TimeResolved-Amplified-Cryptate-Emission (TRACE) technology on the Kryptor Compact analyzers (B.R.A.H.M.S.
GmbH, Henningsdorf, Germany). NT-proBNP levels were determined with an electrochemiluminescence
immunoassay on a Modular platform (Roche Diagnostics, Bsel, Switzerland). Cardiac troponin T (cTnT) levels
were measured with a highly sensitive assay on an autoanalyzer (cobas e 411, Roche Diagnostics, Penzberg,
Germany).
Outcomes
All clinical events were confirmed by a review of medical records. Cardiovascular death, MI, and stroke
underwent blinded review by an outcomes committee. Heart failure was classified by centrally trained local
staff and confirmed by staff at the coordinating center through a review of hospital records. For an event to be
classified as heart failure, hospitalization with a primary cause of heart failure was required.
Statistical analyses
As described by Pencina and colleagues, the integrated discrimination improvement (IDI) is a method to
quantify the differences in the probabilities for events and non-events based on the addition of the new
biomarkers to the model and can be viewed as difference between the improvement in average sensitivity and
any potential increase in average “one minus specificity”. The net re-classification improvement (NRI) is the
probability that patients are appropriately assigned to a higher or lower risk. We calculated NRI using Harrell’s
technique, as programmed in R, which evaluates the change in the estimated risk as a continuous variable and
therefore is not dependent on a priori categorization.
3
Sabatine: Biomarkers of Cardiovascular Stress in Stable CAD
Supplemental Table 1. Baseline Characteristics of Patients in the PEACE Trial
Baseline Characteristic
All patients
(n=8290)
Patients in the
biomarker substudy
(n=3717)
Patients not in the
biomarker substudy
(n=4573)
64.3 8.2
64.1 8.2
64.5 8.2
Female sex
1494 (18.0)
701 (18.9)
793 (17.3)
Weight, kg
83.4 15.7
83.9 15.7
83.1 15.7
Hypertension
3764 (45.4)
1658 (44.6)
2106 (46.1)
Diabetes
1380 (16.7)
602 (16.2)
778 (17.0)
Current smoker
1177 (14.2)
564 (15.2)
613 (13.4)
Prior MI
4552 (55.0)
2087 (56.2)
2465 (54.0)
Prior PCI or CABG
5971 (72.1)
2697 (72.6)
3274 (71.7)
Aspirin
7519 (90.7)
3389 (91.2)
4130 (90.4)
Beta-blocker
4965 (59.9)
2303 (62.0)
2662 (58.3)
Lipid-lowering therapy
5801 (70.0)
2667 (71.8)
3134 (68.6)
SBP, mmHg
133.4 16.6
133.4 16.8
133.5 16.4
DBP, mmHg
77.7 9.7
78.1 10.0
77.4 9.6
GFR, ml/min/1.73 m2
77.6 19.1
77.9 19.4
77.3 18.8
ApoB, mg/dl
107.2 23.1
107.2 23.1
106.8 26.3
ApoA, mg/dl
138.2 24.6
138.2 24.6
133.2 21.4
58.2 9.4
58.7 9.6
57.7 9.1
Age, y
LVEF, %
Data presented are mean SD for normally distributed continuous variables and n (%) for dichotomous
variables. CABG = coronary artery bypass grafting; DBP = diastolic blood pressure; GFR = glomerular
filtration rate; LVEF = left ventricular ejection fraction; MI = myocardial infarction; PCI = percutaneous
coronary intervention; SBP = systolic blood pressure.
4
Sabatine: Biomarkers of Cardiovascular Stress in Stable CAD
Supplemental Table 2. Biomarker Assay Specifications
Biomarker
MR-proANP
MR-proADM
CT-proET-1
Copeptin
pmol/L
nmol/L
pmol/L
pmol/L
2.1
0.05
3
5
1000
10
500
500
Assay specifications
Units of
measurement
Detection limit
Direct
measurement upper
limit
Coefficient of
variation
20-80 pmol/L: <8%
0.2-0.5 nmol/L: <20% 40-80 pmol/L: <10%
15-20 pmol/L: <15%
>80 pmol/L: <5%
0.5-2.0 nmol/L: <11% >80 pmol/L: <6%
20-50 pmol/L: <13%
2-6 nmol/L: <10%
>50 pmol/L: <8%
>6 nmol/L: <6%
Values in Healthy
Population*
Median
46.1
0.39
45.5
5.0
97.5 percentile
163.9
0.52
73.9
17.4
Median
(25th-75th %ile)
90.45
(63.68-128.3)
0.5301
(0.4486-0.6353)
47.82
(39.04-57.02)
6.467
(0-10.67)
Mean±SD of log
transformed values†
4.627±0.460
2.356±0.016
4.036±0.301
2.765±0.422
206
(127-322)
0.75
(0.58-0.97)
81
(64-105)
13.8
(7.6-24.2)
Values in PEACE
Values in Heart
Failure Population1
Median
(25th-75th %ile)
*
Data are from the package inserts for each assay.
Raw values were natural log transformed. For MR-proADM, as the raw values were <1, a constant (10) was added to all values prior
to log transformation.
†
5
Sabatine: Biomarkers of Cardiovascular Stress in Stable CAD
Supplemental Table 3. Baseline Characteristics by MR-proANP Quartiles
Quartiles of MR-proANP (pmol/L)
Baseline
Characteristic
63.68
63.69-90.45
90.46-128.3
128.4
(n=930)
(n=929)
(n=930)
(n=928)
59.5 6.8
62.1 7.3
65.3 7.5
69.6 7.4
<0.001
Female sex
140 (15.1)
160 (17.2)
193 (20.8)
208 (22.4)
<0.001
Weight, kg
87.5 16.0
84.8 15.0
83.1 15.7
80.4 15.1
<0.001
Hypertension
363 (39.0)
376 (40.5)
447 (48.1)
472 (50.9)
<0.001
Diabetes
179 (19.2)
152 (16.4)
135 (14.5)
136 (14.7)
0.004
Current smoker
228 (24.5)
165 (17.8)
95 (10.2)
76 (8.2)
<0.001
Prior MI
519 (55.8)
517 (55.7)
510 (54.9)
541 (58.3)
0.36
Prior PCI or CABG
661 (71.1)
676 (72.8)
669 (72.0)
691 (74.5)
0.15
Aspirin
865 (93.0)
865 (93.1)
842 (90.7)
817 (88.0)
<0.001
Beta-blocker
419 (45.1)
531 (57.2)
646 (69.6)
707 (76.2)
<0.001
Lipid-lowering therapy
681 (73.3)
692 (74.5)
661 (71.2)
633 (68.2)
0.005
SBP, mmHg
130.7 14.7
131.6 16.2
133.9 16.9
137.3 18.5
<0.001
DBP, mmHg
80.0 9.8
78.2 10.1
77.6 9.6
76.7 10.1
<0.001
GFR, ml/min/1.73 m2
84.8 20.6
80.6 18.6
76.1 17.2
70.2 17.9
<0.001
ApoB, mg/dl
109.8 23.4
108.2 23.8
106.0 22.3
104.7 22.4
<0.001
ApoA, mg/dl
137.2 23.4
137.3 23.6
139.3 25.0
139.2 26.3
0.12
59.5 9.6
59.3 9.6
58.7 9.8
57.5 9.4
<0.001
Age, y
LVEF, %
P value
Data presented are mean SD for normally distributed continuous variables and n (%) for dichotomous variables.
BMI = body mass index; CABG = coronary artery bypass grafting; DBP = diastolic blood pressure; GFR =
glomerular filtration rate; LVEF = left ventricular ejection fraction; MI = myocardial infarction; PCI =
percutaneous coronary intervention; SBP = systolic blood pressure.
6
Sabatine: Biomarkers of Cardiovascular Stress in Stable CAD
Supplemental Table 4. Baseline Characteristics by MR-proADM Quartiles
Quartiles of MR-proADM (nmol/L)
Baseline
Characteristic
0.4486
0.4487-0.5301
0.5302-0.6353
0.6354
(n=930)
(n=930)
(n=928)
(n=929)
Age, y
60.1
Female sex
148 (15.9)
125 (13.4)
Weight, kg
80.6
83.8
Hypertension
377 (40.5)
350 (37.6)
Diabetes
148 (15.9)
Current smoker
P value
7.6
<0.001
173 (18.6)
255 (27.4)
<0.001
85.1
86.3
16.8
<0.001
435 (46.9)
496 (53.4)
<0.001
133 (14.3)
139 (15.0)
182 (19.6)
0.03
145 (15.6)
130 (14.0)
160 (17.2)
129 (13.9)
0.75
Prior MI
506 (54.4)
534 (57.4)
526 (56.7)
521 (56.1)
0.54
Prior PCI or CABG
705 (75.8)
688 (74.0)
649 (69.9)
655 (70.6)
0.003
Aspirin
863 (92.8)
866 (93.1)
840 (90.6)
820 (88.4)
<0.001
Beta-blocker
525 (56.5)
554 (59.6)
601 (64.8)
623 (67.1)
<0.001
Lipid-lowering therapy
713 (76.8)
689 (74.1)
649 (70.1)
616 (66.4)
<0.001
7.0
14.5
62.5
7.6
14.6
65.2
7.8
16.0
68.7
131.0
16.3
134.5
16.9
136.6
17.4
<0.001
10.2
77.9
9.8
78.5
9.6
77.2
10.6
0.01
84.9
20.0
81.2
18.5
77.4
17.2
68.2
17.6
<0.001
ApoB, mg/dl
106.9
21.7
106.2
22.2
108.5
24.8
107.2
23.4
0.64
ApoA, mg/dl
138.1
24.5
136.7
23.3
138.4
24.4
139.7
26.1
0.08
58.9
9.6
58.6
9.4
59.0
9.9
58.5
9.7
0.39
SBP, mmHg
131.4
DBP, mmHg
78.8
GFR, ml/min/1.73m2
LVEF, %
16.1
See footnote to Supplemental Table 3 for details.
7
Sabatine: Biomarkers of Cardiovascular Stress in Stable CAD
Supplemental Table 5. Baseline Characteristics by CT-proET-1 Quartiles
Quartiles of CT-proET-1 (pmol/L)
Baseline
Characteristic
39.04
39.05-47.82
47.83-57.02
57.03
(n=930)
(n=929)
(n=929)
(n=929)
62.0 7.6
63.1 8.0
64.6 8.2
66.8 8.0
<0.001
Female sex
191 (20.5)
155 (16.7)
145 (15.6)
210 (22.6)
0.37
Weight, kg
82.3 15.5
84.3 15.4
84.4 15.4
84.8 16.1
0.001
Hypertension
384 (41.3)
385 (41.4)
403 (43.4)
486 (52.3)
<0.001
Diabetes
162 (17.4)
125 (13.5)
153 (16.5)
162 (17.4)
0.57
Current smoker
127 (13.7)
132 (14.2)
140 (15.1)
165 (17.8)
0.01
Prior MI
493 (53.0)
551 (59.3)
516 (55.6)
527 (56.7)
0.31
Prior PCI or CABG
701 (75.4)
685 (73.7)
647 (69.7)
664 (71.5)
0.02
Aspirin
859 (92.4)
854 (91.9)
852 (91.9)
824 (88.7)
0.008
Beta-blocker
557 (59.9)
567 (61.0)
573 (61.8)
606 (65.2)
0.02
Lipid-lowering therapy
699 (75.2)
676 (72.8)
650 (70.1)
642 (69.1)
0.001
SBP, mmHg
131.1 16.1
132.9 16.5
133.4 17.2
136.0 17.2
<0.001
DBP, mmHg
77.8 9.7
78.7 10.1
78.4 9.6
77.7 10.4
0.61
GFR, ml/min/1.73 m2
84.6 21.2
80.6 17.3
76.9 17.9
69.6 17.6
<0.001
ApoB, mg/dl
106.0 22.6
107.0 22.0
107.0 23.3
108.7 24.3
0.04
ApoA, mg/dl
139.6 25.3
139.1 24.5
137.3 24.7
136.9 23.8
0.01
58.7 9.5
59.2 9.7
58.8 9.7
58.3 9.7
0.21
Age, y
LVEF, %
See footnote to Supplemental Table 3 for details.
8
P value
Sabatine: Biomarkers of Cardiovascular Stress in Stable CAD
Supplemental Table 6. Baseline Characteristics by Copeptin Quartiles
Quartiles of Copeptin (pmol/L)
Baseline
Characteristic
0
5-6.467
6.468-10.67
10.68
(n=1382)
(n=477)
(n=929)
(n=929)
63.7 7.9
63.7 8.3
63.4 8.2
65.7 8.3
<0.001
Female sex
342 (24.8)
89 (18.7)
143 (15.4)
127 (13.7)
<0.001
Weight, kg
82.3 15.2
84.6 15.9
84.6 15.9
85.4 15.7
<0.001
Hypertension
629 (44.1)
218 (45.7)
380 (40.9)
451 (48.6)
0.20
Diabetes
205 (14.8)
78 (16.4)
135 (14.5)
184 (19.8)
0.01
Current smoker
183 (13.2)
64 (13.4)
176 (19.0)
141 (15.2)
0.02
Prior MI
754 (54.6)
268 (56.2)
539 (58.0)
526 (56.7)
0.18
Prior PCI or CABG
1011 (73.2)
338 (70.9)
684 (73.6)
664 (71.6)
0.60
Aspirin
1273 (92.1)
439 (92.0)
853 (91.9)
824 (88.8)
0.02
Beta-blocker
849 (61.4)
292 (61.2)
583 (62.8)
579 (62.4)
0.52
Lipid-lowering therapy
1006 (72.9)
348 (73.0)
666 (71.8)
647 (69.7)
0.11
SBP, mmHg
132.7 16.9
134.3 17.0
132.0 16.4
135.3 16.9
0.01
DBP, mmHg
77.9 9.8
78.9 9.9
78.2 10.1
78.0 10.2
0.99
GFR, ml/min/1.73 m2
80.0 18.8
78.9 18.9
78.6 20.0
73.7 19.3
<0.001
ApoB, mg/dl
107.0 23.1
108.1 24.0
105.8 21.7
108.4 23.8
0.67
ApoA, mg/dl
140.4 25.7
138.2 23.0
137.6 24.1
135.7 23.9
<0.001
59.3 9.7
58.4 9.1
58.6 9.6
58.3 9.7
0.01
Age, y
LVEF, %
See footnote to Supplemental Table 3 for details.
9
P value
Sabatine: Biomarkers of Cardiovascular Stress in Stable CAD
Supplemental Table 7. Correlation between biomarkers
MR-proANP MR-proADM
CT-proET-1
Copeptin
NT-proBNP
cTnT
MR-proANP
...
0.44
0.30
0.12
0.76
0.37
MR-proADM
<0.001
...
0.63
0.23
0.38
0.30
CT-proET-1
<0.001
<0.001
...
0.21
0.25
0.22
Copeptin
<0.001
<0.001
<0.001
...
0.10
0.20
NT-proBNP
<0.001
<0.001
<0.001
<0.001
...
0.35
cTnT
<0.001
<0.001
<0.001
<0.001
<0.001
...
Values above and to the right of the diagonal line of identity are Spearman’s correlation coefficients, values to the left and
below are the corresponding P values.
10
Sabatine: Biomarkers of Cardiovascular Stress in Stable CAD
Supplemental Table 8. Association of biomarker levels and individual components of primary outcome in the
placebo arm
CV Death
Biomarker
Heart Failure
Model
HR (95% CI)
P value
HR (95% CI)
P value
Unadjusted
2.12
(1.69-2.67)
<0.001
2.52
(1.96-3.23)
<0.001
Adjusted
1.76
(1.31-2.37)
<0.001
2.35
(1.72-3.20)
<0.001
Unadjusted
1.74
(1.52-1.99)
<0.001
1.68
(1.44-1.96)
<0.001
Adjusted
1.56
(1.27-1.90)
<0.001
1.47
(1.17-1.84)
0.001
Unadjusted
2.07
(1.55-2.77)
<0.001
2.13
(1.55-2.93)
<0.001
Adjusted
1.52
(1.10-2.10)
0.012
1.70
(1.20-2.42)
0.003
Unadjusted
1.29
(1.03-1.62)
0.026
1.23
(0.96-1.58)
0.10
Adjusted
1.03
(0.80-1.32)
0.83
1.08
(0.83-1.40)
0.57
MR-proANP
MR-proADM
CT-proET-1
Copeptin
Of the 1868 patients allocated to placebo, 67 experienced cardiovascular death and 56 heart failure.
HR is per 1-SD increase in the log-transformed value of the biomarker. Each biomarker was
analyzed separately.
11
Sabatine: Biomarkers of Cardiovascular Stress in Stable CAD
Supplemental Table 9. Association of biomarker levels and other outcomes in the placebo arm
All-Cause Death
Biomarker
Acute MI
Acute Stroke
Revascularization
Model
HR (95% CI)
P value
HR (95% CI)
P value
HR (95% CI)
P value
HR (95% CI)
P value
Unadjusted
1.59
(1.37-1.86)
<0.001
1.10
(0.91-1.33)
0.31
1.50
(1.11-2.03)
0.008
0.96
(0.87-1.06)
0.44
Adjusted
1.30
(1.06-1.58)
0.011
1.07
(0.84-1.35)
0.59
1.51
(1.01-2.24)
0.043
0.96
(0.84-1.10)
0.55
Unadjusted
1.57
(1.41-1.74)
<0.001
1.27
(1.08-1.50)
0.003
1.12
(0.84-1.51)
0.44
0.98
(0.88-1.09)
0.72
Adjusted
1.41
(1.22-1.64)
<0.001
1.19
(0.96-1.48)
0.11
0.91
(0.65-1.27)
0.58
0.95
(0.84-1.08)
0.43
Unadjusted
1.56
(1.29-1.89)
<0.001
1.25
(1.00-1.55)
0.046
0.94
(0.69-1.27)
0.69
0.92
(0.83-1.02)
0.12
Adjusted
1.29
(1.05-1.59)
0.016
1.12
(0.89-1.40)
0.35
0.84
(0.63-1.12)
0.23
0.91
(0.81-1.01)
0.08
Unadjusted
1.23
(1.06-1.44)
0.007
1.11
(0.92-1.33)
0.27
0.92
(0.67-1.28)
0.64
1.00
(0.90-1.11)
0.96
Adjusted
1.06
(0.90-1.26)
0.48
1.01
(0.83-1.24)
0.88
0.84
(0.60-1.17)
0.30
0.98
(0.88-1.10)
0.78
MR-proANP
MR-proADM
CT-proET-1
Copeptin
Of the 1868 patients allocated to placebo, 153 died from any cause, 109 had an acute MI, 40 had an acute stroke, and 372 underwent coronary
revascularization. HR is per 1-SD increase in the log-transformed value of the biomarker. Each biomarker was analyzed separately.
12
Sabatine: Biomarkers of Cardiovascular Stress in Stable CAD
Supplemental Table 10. Adjusted multivariable, multimarker models in the placebo arm
Model 3
Model 1
Model 2
Clinical factors +
NT-proBNP
Clinical factors +
cTnT
Model 4
Clinical factors +
NT-proBNP &
cTnT
Model 6
Model 5
Clinical factors +
Clinical factors +
Clinical factors +
NT-proBNP, cTnT,
NT-proBNP, cTnT, NT-proBNP, cTnT,
MR-proANP, &
& MR-proANP
& MR-proADM
MR-proADM
HR
HR
HR
HR
HR
HR
P value
P value
P value
P value
P value
P value
(95% CI)
(95% CI)
(95% CI)
(95% CI)
(95% CI)
(95% CI)
NT-proBNP
1.73
<0.001
(1.42-2.12)
n/a
n/a
1.68
1.22
<0.001
(1.35-2.08)
(0.89-1.68)
1.37
1.21
<0.001
(1.18-1.60)
(1.02-1.44)
cTnT
n/a
n/a
MR-proANP
n/a
n/a
n/a
n/a
MR-proADM
n/a
n/a
n/a
n/a
0.21
1.58
1.22
<0.001
(1.27-1.97)
(0.89-1.67)
0.22
0.026
1.22
(1.02-1.45)
0.027
1.15
(0.96-1.38)
0.14
1.15
(0.96-1.38)
0.14
n/a
n/a
1.59
(1.14-2.22)
0.007
n/a
n/a
1.50
(1.06-2.12)
0.021
n/a
n/a
n/a
n/a
1.25
(1.04-1.50)
0.017
1.20
(0.99-1.44)
0.06
Each model contains the standard clinical factors used in prior models (age, sex, weight, history of hypertension, history of diabetes mellitus, current tobacco
use, prior MI, prior PCI or CABG, systolic blood pressure, estimated GFR, ratio of apoB/apoA, LVEF, aspirin use, beta-blocker use, lipid-lowering
medication use) as well as those biomarkers shown with data. HR is for the risk per 1-SD of log-transformed biomarker.
13
Sabatine: Biomarkers of Cardiovascular Stress in Stable CAD
Supplemental Table 11. C-statistics in adjusted multimarker models in the placebo arm
Without MR-proANP,
MR-proADM, CT-proET-1
Clinical model
alone
Clinical
+ NT-proBNP
Clinical
+ cTnT
Clinical
+ NT-proBNP
+ cTnT
With MR-proANP,
MR-proADM, CT-proET-1
0.768
0.809
P=0.0005
0.793
0.810
P=0.02
P=0.03
P=0.82
0.783
0.810
P=0.03
P=0.49
0.797
0.810
P=0.0004
P=0.63
P=0.007
P=0.03
Each model contains standard clinical factors (listed in the Methods and in the footnote to Table 3 in the main paper).
P values to the right of c-statistics represent the significance of adding MR-proANP, MR-proADM, and CT-proET-1 to
the model.
P values below the c-statistics represent the significance of adding NT-proBNP, cTnT or both to the model.
14
Sabatine: Biomarkers of Cardiovascular Stress in Stable CAD
Supplemental Figure 1
HR
95% CI
0.80
0.61-1.05
Quartiles 1-3
0.93
0.61-1.41
Quartile 4
0.74
0.51-1.08
Quartiles 1-3
0.86
0.57-1.29
Quartile 4
0.75
0.52-1.10
All Patients
NT-proBNP
cTnT
0.2
0.5
1
2
HR (95% CI) f or ef f ect of trandolapril
on CV death or heart f ailure
15
Sabatine: Biomarkers of Cardiovascular Stress in Stable CAD
Supplemental Figure Legend
Supplemental Figure. Benefit of trandolapril on the risk of the composite of cardiovascular death or heart
failure in 3717 patients from the PEACE trial, categorized as to their levels of biomarkers of cardiovascular
stress. Patients are categorized as to whether their level of each biomarker was in the top quartile (quartile 4) or
not (quartiles 1-3). The P values for interaction were 0.43 and 0.63 for NT-proBNP and cTnT, respectively.
The diamond indicate the effect in the entire biomarker cohort, with the center indicating the point estimate and
the left and right ends indicating the 95% CI. The squares and circles indicate the point estimate and the
horizontal lines indicate the 95% CIs for the effect in each subgroup.
16
Sabatine: Biomarkers of Cardiovascular Stress in Stable CAD
Supplemental References
1.
Masson S, Latini R, Carbonieri E, Moretti L, Rossi MG, Ciricugno S, Milani V, Marchioli R, Struck J,
Bergmann A, Maggioni AP, Tognoni G, Tavazzi L. The predictive value of stable precursor fragments
of vasoactive peptides in patients with chronic heart failure: data from the GISSI-heart failure (GISSIHF) trial. Eur J Heart Fail. 2010;12:338-347.
17
58
새로운 바이오마커가 안정형 협심증 환자에서
심혈관계 위험도와 ACE 저해제의 효과를 예측할 수 있다
강 현 재 교수 서울대학교병원 순환기내과
Summary
배경
혈중 바이오마커는 심혈관계 스트레스를 평가하고, 위
때, 심혈관계 위험도 예측 모델의 예측력을 증가시켰다.
험도 예측에 따른 치료 선택에 도움을 줄 수 있다.
그리고 trandolapril의 투여는 바이오마커가 2가지 이
상 증가(가장 높은 사분위 군에 포함된 경우)된 환자에
방법 및 결과
서 심혈관계 사망이나 심부전으로 인한 입원의 위험도
PEACE(Prevention of Events With Angiotensin
를 유의하게 낮추었으나(HR, 0.53; 95% CI, 0.36–0.80),
Converting Enzyme) 연구에 참여한 좌심실 수축기 기
바이오마커가 1개 이하로 증가된 소견을 보인 환자에
능이 유지되는 3,717명의 안정형 협심증 환자를 대상
서는 그렇지 않았다(HR, 1.09; 95% CI, 0.74–1.59; P for
으로 midregional pro-atrial natriuretic peptide(MR-
interaction=0.012).
proANP), midregional pro-adrenomedullin(MRproADM), C-terminal pro-endothelin-1(CT-proET-1),
결론
and copeptin의 4가지 바이오마커를 측정하였다.
좌심실 수축기 기능이 유지되는 안정형 협심증 환자
임상적인 심혈관계 위험도와 좌심실 수축기 기능을 보
에서 심혈관계 스트레스를 반영하는 새로운 바이오마
정하였을 때, MR-proANP, MR-proADM, CT-proET-1
커의 증가가 심혈관계 사망 또는 심부전의 고위험군을
의 증가가 심혈관계 사망 또는 심부전의 위험과 독립적
구분하는 데 도움을 줄 수 있고, 안지오텐신 전환효소
인 연관성을 보였다(log 변환한 표준편차가 1 증가할 때
(angiotensin-converting enzyme, ACE) 저해제 치료로
마다 HR이 각각 1.97, 1.48, 1.47씩 증가됨; P≤0.002). 이
도움을 받을 수 있는 환자군을 선택하는 데 도움을 줄
3가지 바이오마커는 임상적 예측 모델에 추가하였을
수 있다.
Coronary Artery Disease
Commentary
고위험 환자 혹은 특정 치료에 도움을 받을 환자의 선별
찰된 심혈관계 위험도 감소 효과에 대한 작용 기전을 설
은 환자별 맞춤 치료 및 치료의 최적화를 위해서는 필
명할 수 없고, 바이오마커 측정치의 재현성, 정상인과
수적인 요구사항이다. 환자의 선별과정에서 기능 검사,
의 측정치의 중복성 등은 여전히 해결되어야 할 숙제로
영상 검사나 바이오마커의 측정과 같은 표지자 검사가
남아있다. 실제로 많은 바이오마커들이 연구단계에서
기존의 임상적 예측모델을 대체할 수 있거나 임상적 예
는 가능성을 인정받지만, 실제 임상에서 적용되지 못하
측 모델의 예측력을 유의하게 개선할 수 있다면, 환자
는 가장 큰 문제 중 하나가 정상인과 고위험군의 선별능
진료 및 고위험군의 질병 발생 예방에 매우 중요한 역할
력에 있다고 판단된다. 즉, 기존의 임상적인 판단만으로
을 할 수 있을 것이다. 이 같은 기대를 바탕으로 많은 예
대부분의 고위험군을 구별할 수 있으므로, 결국 대상자
측 지표에 대한 연구와 평가가 진행되고 있다. 그러나 실
는 임상적으로 중등도 혹은 저위험군에 해당하는 환자
제로 BNP(B-type natriuretic peptide)와 같이 성공적으
에 국한하게 된다. 상대적으로 위험도가 낮은 환자들의
로 임상진료에 적용되고 있는 소수의 예를 제외하고는
경우에는 위험도 선별에 따른 예후의 개선 정도가 작을
대부분이 실제 진료에는 도움을 주지 못하고, 학술적 연
수밖에 없고, 정상군과 검사 결과가 겹치는 부분이 많을
구 단계에 머물러 있는 경우가 대부분이다. 이 같은 새
수밖에 없다는 근본적인 한계점을 가지고 있다. 궁극적
로운 바이오마커들이 진료에 이용되기 위해서는 병태생
으로는 전향적 연구를 포함한 다른 환자군에서의 재현
리적인 기전의 타당성 검증에서부터 측정법의 타당성,
성 평가가 반드시 필요하다고 하겠다.
측정값의 분포 및 목표 대상군의 선별 능력, 임상경과의
이 같은 현실적인 제한점들에도 불구하고 본 연구는 바
예측력 그리고 가능하면 치료 효과의 예측력과 경제적
이오마커를 기반으로 한 위험도 평가가 심혈관계 위험
타당성이 확보되어야 한다.
도를 예측하고, 치료 여부에 대한 가이드라인을 제시할
본 연구에서는 가능성을 인정받고 있는 4가지 새로운
수 있다는 좀 더 진일보된 가능성을 보여주었다는 점에
바이오마커를 ACE 저해제의 투약 여부가 무작위로 배
서 의의가 있다.
정된 기존의 무작위배정 임상연구에 참여한 대규모 환
자군에서 전향적으로 채집된 검체를 이용하여 수행되
었다. 전향적으로 수집된 임상 경과에 대한 영향을 다
각적인 분석을 통하여 위험도 평가 및 ACE 저해제의 임
상 적용의 가능성을 제시하였다는 데 의의가 있다고 하
겠다. 특히, 모집단인 PEACE 연구에서는 ACE 저해제를
사용하여 심혈관 위험도 감소 효과를 입증하지 못했던
점에 비해, 바이오마커를 통해 선별한 고위험군에서는
ACE 저해제 사용 시 유의한 위험도 감소 효과가 관찰됨
은 추후 바이오마커의 활용 가능성을 보여주었다는 측
면에서 주목을 받을 만하다. 그러나 현재로서는 ACE 저
해제를 투여받은 바이오마커가 증가된 환자군에서 관
Reference
111 Richards AM, Doughty R, Nicholls MG, MacMahon S, Sharpe N, Murphy J, Espiner
EA, Frampton C, Yandle TG; Australia-New Zealand Heart Failure Group. Plasma
N-terminal pro-brain natriuretic peptide and adrenomedullin: prognostic utility and
prediction of benefit from carvedilol in chronic ischemic left ventricular dysfunction:
Australia-New Zealand Heart Failure Group. J Am Coll Cardiol. 2001;37:1781-1787.
59
Coronary Heart Disease
Evaluation of Multiple Biomarkers of Cardiovascular Stress
for Risk Prediction and Guiding Medical Therapy in
Patients With Stable Coronary Disease
Marc S. Sabatine, MD, MPH; David A. Morrow, MD, MPH; James A. de Lemos, MD;
Torbjorn Omland, MD, PhD; Sarah Sloan, MS; Petr Jarolim, MD, PhD; Scott D. Solomon, MD;
Marc A. Pfeffer, MD, PhD; Eugene Braunwald, MD
Background—Circulating biomarkers can offer insight into subclinical cardiovascular stress and thus have the potential to
aid in risk stratification and tailoring of therapy.
Methods and Results—We measured plasma levels of 4 cardiovascular biomarkers, midregional pro-atrial natriuretic peptide
(MR-proANP), midregional pro-adrenomedullin (MR-proADM), C-terminal pro-endothelin-1 (CT-proET-1), and copeptin,
in 3717 patients with stable coronary artery disease and preserved left ventricular ejection fraction who were randomized to
trandolapril or placebo as part of the Prevention of Events With Angiotensin Converting Enzyme (PEACE) trial. After
adjustment for clinical cardiovascular risk predictors and left ventricular ejection fraction, elevated levels of MR-proANP,
MR-proADM, and CT-proET-1 were independently associated with the risk of cardiovascular death or heart failure (hazard
ratios per 1-SD increase in log-transformed biomarker levels of 1.97, 1.48, and 1.47, respectively; P�0.002 for each
biomarker). These 3 biomarkers also significantly improved metrics of discrimination when added to a clinical model.
Trandolapril significantly reduced the risk of cardiovascular death or heart failure in patients who had elevated levels of �2
biomarkers (hazard ratio, 0.53; 95% confidence interval, 0.36 – 0.80), whereas there was no benefit in patients with elevated
levels of 0 or 1 biomarker (hazard ratio, 1.09; 95% confidence interval, 0.74 –1.59; Pinteraction�0.012).
Conclusions—In patients with stable coronary artery disease and preserved left ventricular ejection fraction, our results
suggest that elevated levels of novel biomarkers of cardiovascular stress may help identify patients who are at higher
risk of cardiovascular death and heart failure and may be useful to select patients who derive significant benefit from
angiotensin-converting enzyme inhibitor therapy. (Circulation. 2012;125:233-240.)
Key Words: angiotensin-converting enzyme inhibitors � biomarkers � coronary disease
E
relation to cardiomyocyte and/or vascular stress offers the
potential for more refined risk assessment. Specifically, atrial
natriuretic peptide (ANP) is a vasodilator and natriuretic that
is synthesized in the myocardium in response to increased
wall tension.8 Adrenomedullin (ADM) is a potent vasodilator
synthesized in the adrenal medulla, vascular endothelial cells,
heart, and elsewhere in response to physical stretch and
specific cytokines, with levels in the heart elevated in the
setting of pressure and volume overload.9,10 Endothelin-1
(ET-1) is a potent vasoconstrictor and profibrotic hormone
that is secreted by vascular endothelial cells, with levels
correlating with shear stress and pulmonary artery pressure.11
Copeptin is a stable peptide derived from the precursor to
levated levels of circulating biomarkers related to cardiac
volume or pressure overload offer insight into subclinical
cardiac stress and thus have the potential to aid in risk
stratification.1 Specifically, elevated levels of B-type natriuretic peptide (BNP; either the hormone or the aminoterminal fragment of the prohormone [NT-proBNP]) have
been shown to be predictive of mortality and/or heart failure
events across a broad range of individuals, ranging from the
general population to patients with overt heart failure.1–7
Clinical Perspective on p
Development of newer assays that target more stable
epitopes of hormones or prohormones that are released in
Received August 24, 2011; accepted December 7, 2011.
From the TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital and Department of Medicine, Harvard Medical School, Boston,
MA (M.S.S., D.A.M., S.S., E.B.); Division of Cardiology, University of Texas Southwestern Medical Center, Dallas (J.A.d.L.); Division of Medicine,
Akershus University Hospital and Center for Heart Failure Research and KG Jebsen Cardiac Research Center, University of Oslo, Oslo, Norway (T.O.);
Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA (P.J.); and Cardiovascular Division, Brigham and
Women’s Hospital, Harvard Medical School, Boston, MA (S.D.S., M.A.P.).
Guest Editor for this article was Gregg C. Fonarow, MD.
The online-only Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.
111.063842/-/DC1.
Correspondence to Marc S. Sabatine, MD, MPH, TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital, 350 Longwood Ave,
Boston, MA 02115. E-mail [email protected]
© 2011 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org
DOI: 10.1161/CIRCULATIONAHA.111.063842
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233 by IMED Korea on April 23, 2012
60
61
234
Circulation
January 17, 2012
arginine vasopressin, a vasoconstrictor that is secreted from
the posterior pituitary in response not only to osmotic stimuli
but also to hemodynamic changes detected by cardiac and
vascular baroreceptors.12 Higher levels of these biomarkers
have been associated with an increased risk of death and/or
heart failure events in patients with established heart failure.13–16 The availability of an assay panel for these 4
biomarkers of cardiovascular stress that have shown promise
in patients with established heart failure created the opportunity to investigate their utility in a broader population.
Angiotensin-converting enzyme (ACE) inhibitors substantially reduce the risk of death and heart failure events in patients
with heart failure, with the greatest benefit in those patients with
the most clinically severe heart failure.17 Among patients with
acute myocardial infarction (MI), the benefit of ACE inhibitors
is greatest in those with high-risk clinical features such as
anterior MI or depressed left ventricular systolic function.18 In
contrast, the role of ACE inhibitors in lower-risk patients with
stable coronary artery disease (CAD) without heart failure is less
clear.19 –21 We explored the hypotheses that in such patients,
elevated levels of midregional (MR) pro-ANP, MR-proADM,
C-terminal proET-1 (CT-proET-1), and copeptin would offer
prognostic value for cardiovascular death and heart failure
independently of clinical risk factors and would identify patients
who derive greater clinical benefit from the use of an ACE
inhibitor. We tested these hypotheses by measuring plasma
levels of these novel biomarkers of cardiovascular stress in 3717
patients with stable CAD and preserved left ventricular ejection
fraction (LVEF) who were randomized to trandolapril or placebo as part of the Prevention of Events With Angiotensin
Converting Enzyme (PEACE) trial.
Methods
Patient Population
This study involved 3717 patients with documented stable CAD who
had been enrolled in the PEACE trial (www.ClinicalTrials.gov;
unique identifier, NCT00000558) and provided a sample of blood at
the time of enrollment. The design and main outcomes of the PEACE
trial have been published previously,21 and salient features are
detailed in the Methods section and Table I in the online-only Data
Supplement. In brief, subjects were free of heart failure at baseline,
and none had been hospitalized with an acute coronary syndrome or
had undergone coronary revascularization within the 3 months
preceding trial entry. Both the parent clinical trial and this substudy
were approved by the relevant institutional review boards, and
informed consent was obtained from all patients.
Biomarker Analyses
Baseline plasma levels of MR-proANP, MR-proADM, CTproET-1,24 and copeptin25 (assays from B.R.A.H.M.S. GmbH, Henningsdorf, Germany) were determined in the Thrombolysis in Myocardial Infarction (TIMI) Clinical Trials Laboratory (Boston, MA) as
detailed in the Methods section and Table II in the online-only Data
Supplement. Baseline levels of NT-proBNP and cardiac troponin T
(cTnT) measured with a highly sensitive assay had been determined
in this population, as previously published and summarized in the
Methods section in the online-only Data Supplement.6,26 All testing
was performed by personnel blinded to clinical outcomes and
treatment allocation.
22
23
Outcomes
On the basis of prior data regarding the predictive ability of
biomarkers of cardiac stress,6 the primary outcome in this analysis
was the composite of cardiovascular death or hospitalization for
heart failure. Additionally, we explored other major adverse cardiovascular events that had been recorded in patients in the trial,
including all-cause death, acute MI, acute stroke, and coronary
revascularization (percutaneous or surgical). Event adjudication is
detailed in the Methods section in the online-only Data Supplement.
All clinical events were classified before biomarkers were measured.
Statistical Analyses
Baseline characteristics are reported as mean�SD for normally distributed continuous variables and as counts and percentages for categorical
variables. Wilcoxon rank-sum and �2 tests for trend were used to test for
differences in continuous and categorical baseline characteristics between quartiles of biomarkers. The Spearman correlation was used to
calculate the association between different biomarkers and categorized
based on standard cut points.27 The cumulative incidences of clinical
outcomes across quartiles of each biomarker were compared by use of
a log-rank test. Cox proportional-hazards models were used to examine
the association between biomarker levels and outcome data. In these
models, biomarker levels were examined both as a continuous variable
(after natural logarithmic transformation) and as a categorical variable
by quartiles. Associations were adjusted for age, sex, weight, history of
hypertension, history of diabetes mellitus, current tobacco use, prior MI,
prior percutaneous coronary intervention or coronary artery bypass
grafting, systolic blood pressure, estimated glomerular filtration rate,
ratio of apolipoprotein B to apolipoprotein A, LVEF, aspirin use,
�-blocker use, and lipid-lowering medication use. Starting with a model
containing the aforementioned clinical covariates, a forward selection
algorithm (P�0.05 to enter the model) was used to select among the 4
novel biomarkers, as well as NT-proBNP and cTnT. The incremental
performance of the biomarkers in addition to clinical predictors was
further evaluated by calculating changes in the C statistic, integrated
discrimination improvement, and category-free net reclassification improvement metrics (see the Methods section in the online-only Data
Supplement for further details).28 –30
To examine for heterogeneity in the effect of trandolapril on the risk
of cardiovascular death or heart failure, hazard ratios (HRs) were
calculated in patients who were and were not in the highest-risk category
as defined by being in the top quartile of a biomarker level. To test for
statistically significant effect modification, a Cox proportional hazards
model was created that included a term for trandolapril, a term for
biomarker risk category, and an interaction term.
A value of P�0.05 was considered to indicate statistical significance,
and all tests were 2 sided. No adjustment for multiple comparisons was
performed. Although based on previous work with these biomarkers in
other populations, all of the analyses we have performed in this
biomarker substudy are inherently exploratory. Analyses were performed with STATA/IC (version 10.1, STATA Corp, College Station,
TX) and R (version 2.12.1).
Results
Baseline Characteristics of the Patients and
Biomarker Levels
Baseline measurements of the 4 novel biomarkers were available
for 3717 patients from the PEACE trial. The clinical characteristics of the patients are given in Table 1. By design, all patients
had stable CAD, and LVEF was preserved at a mean�SD value
of 58.7�9.6%. Median levels of MR-proANP, MR-proADM,
CT-proET-1, and copeptin at baseline in patients in the PEACE
trial were 90.45 pmol/L (25th–75th percentile, 63.68–128.3
pmol/L), 0.53 nmol/L (25th–75th percentile, 0.45–0.64 nmol/L),
47.82 pmol/L (25th–75th percentile, 39.04–57.02 pmol/L), and
6.47 pmol/L (25th–75th percentile, 0–10.67 pmol/L), respectively. The levels tended to be higher than those seen in healthy
populations, but with the exception of MR-proADM, the majority of values were lower than the 97.5th percentile reported in
healthy populations and lower than the values in patients with
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62
Sabatine et al
Table 1.
Biomarkers of Cardiovascular Stress in Stable CAD
Baseline Characteristics of Patients
Baseline Characteristic
All
Patients, n
Placebo
3717
1868
1849
64.1�8.2
64.1�8.2
64.2�8.1
Female sex, n (%)
701 (18.9)
334 (17.9)
367 (19.9)
Weight, kg
83.9�15.7
83.7�15.7
84.2�15.6
1658 (44.6)
835 (44.7)
823 (44.5)
602 (16.2)
294 (15.7)
308 (16.7)
Hypertension, n (%)
Diabetes mellitus, n (%)
Current smoker, n (%)
Prior MI, n (%)
564 (15.2)
290 (15.5)
274 (14.8)
2087 (56.2)
1076 (57.6)
1011 (54.7)
Prior PCI or CABG, n (%)
2697 (72.6)
1367 (73.2)
1330 (72.0)
Aspirin use, n (%)
3389 (91.2)
1721 (92.2)
1668 (90.3)
�-blocker use, n (%)
2303 (62.0)
1156 (61.9)
1147 (62.1)
Lipid-lowering therapy use, n (%)
2667 (71.8)
1334 (71.5)
1333 (72.2)
SBP, mm Hg
133.4�16.8 133.4�16.8 133.3�16.8
DBP, mm Hg
�1
GFR, mL � min
�2
� 1.73 m
78.1�10.0
78.2�10.2
78.0�9.8
77.9�19.4
78.3�19.4
77.6�19.3
ApoB, mg/dL
107.2�23.1 107.6�22.9 106.8�23.2
ApoA, mg/dL
138.2�24.6 138.6�24.5 137.8�24.7
LVEF, %
58.7�9.6
of MR-proANP and NT-proBNP (r�0.76), but correlations of
NT-proBNP and cTnT with other markers were weak (r�0.38;
Table VII in the online-only Data Supplement).
Trandolapril
Age, y
58.7�9.6
Clinical Outcomes
Among patients allocated to the placebo arm of the PEACE trial,
higher baseline levels of each of the 4 novel biomarker of
cardiovascular stress were strongly associated with the subsequent risk of cardiovascular death or heart failure (the composite
of which occurred in 114 patients), with up to approximately a
doubling of the risk per each 1-SD increase in log-transformed
biomarker levels (P�0.002 for each biomarker; Table 2). Risk
increased across quartiles, especially the fourth quartile (Figure
1). Similar associations were seen between biomarker levels and
the risk of cardiovascular death (which occurred in 67 patients)
and of heart failure individually (which occurred in 56 patients;
Table VIII in the online-only Data Supplement).
After adjustment for traditional clinical risk predictors, estimated glomerular filtration rate, and LVEF (see Methods for a
detailed list of covariates), elevated levels of MR-proANP,
MR-proADM, and CT-proET-1 remained significantly associated with an increased risk of cardiovascular death or heart
failure, ranging from 47% higher risk to a near doubling of the
risk per each 1-SD increase in log-transformed biomarker levels
(P�0.002 for each biomarker); in terms of quartile analysis, the
risk was most pronounced for those patients in the top quartile,
who had almost 3 times to �5 times the risk seen for patients in
the lowest quartile. In contrast, after multivariable adjustment,
the association with copeptin was no longer significant (Table
3). As was the case for the unadjusted analyses, similar associations were seen between biomarker levels and the risk of
cardiovascular death and of heart failure individually (Table
VIII in the online-only Data Supplement). Compared with
cardiovascular death, the associations with the less cardiovascular-specific end point of all-cause death were significant
but weaker (Table IX in the online-only Data Supplement).
As expected on the basis of prior work,6,26 there were
nonsignificant adjusted associations between levels of novel
biomarkers of cardiovascular stress and the risk of acute MI,
stroke, or coronary revascularization, with the exception of
MR-proANP and stroke (P�0.043; Table IX in the onlineonly Data Supplement).
58.8�9.7
MI indicates myocardial infarction; PCI, percutaneous coronary intervention;
CABG, coronary artery bypass grafting; SBP, systolic blood pressure; DBP,
diastolic blood pressure; GFR, glomerular filtration rate; ApoB, apolipoprotein B;
ApoA, apolipoprotein A; and LVEF, left ventricular ejection fraction. Data are
presented as mean�SD for normally distributed continuous variables and n (%)
for dichotomous variables.
overt heart failure (Table II in the online-only Data Supplement).
Characteristics of patients according to quartiles of biomarker
levels are shown in Tables III through VI in the online-only Data
Supplement. In general, higher levels of biomarkers of cardiovascular stress were positively associated with greater age and
prevalence of hypertension and lower estimated glomerular
filtration rate. LVEF was inversely associated with MR-proANP
and copeptin levels but differed by only 2.0 and 1.0 absolute
percentage points between the top and bottom quartiles for the 2
biomarkers, respectively. Among the novel biomarkers, the only
moderately strong correlation was between MR-proADM and
CT-proET-1 (r�0.63); the others were moderate to low
(r�0.44; Table VII in the online-only Data Supplement). As
expected, there was a strong positive correlation between levels
Table 2.
235
Association of Biomarker Levels and Clinical Outcomes in the Placebo Arm
Risk for CV Death or Heart Failure
Biomarker
MR-proANP
HR (95% CI) per 1-SD
Increase in Log-Transformed
Biomarker Values
P
1
2
3
4
Multiple Partial
Trend
2.25 (1.89 –2.42)
�0.001
Referent
1.92 (0.85– 4.30)
3.10 (1.46 – 6.59)
7.30 (3.62–14.70)
�0.0001
�0.0001
HR (95% CI) Across Quartiles
P
MR-proADM
1.69 (1.52–1.88)
�0.001
Referent
2.15 (0.88–5.28)
3.65 (1.58–8.45)
10.25 (4.71–22.33)
�0.0001
�0.0001
CT-proET-1
1.96 (1.57–2.44)
�0.001
Referent
2.25 (1.14–4.45)
1.42 (0.68–2.98)
5.07 (2.72–9.44)
�0.0001
�0.0001
Copeptin
1.30 (1.10–1.55)
0.002
Referent
0.88 (0.43–1.79)
1.23 (0.74–2.05)
2.09 (1.32–3.28)
0.0072
0.0013
CV indicates cardiovascular; HR, hazard ratio; CI, confidence interval; MR-proANP, midregional pro-atrial natriuretic peptide; MR-proADM, midregional
pro-adrenomedullin; and CT-proET-1, C-terminal pro-endothelin-1. A total of 114 of the 1868 patients allocated to placebo experienced CV death or heart failure. Each
biomarker was analyzed separately. In quartile analyses, “multiple partial” refers to a 3-df test for the addition of all quartiles and “trend” refers to a 1-df test for
linear trend across quartiles.
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236
Circulation
January 17, 2012
Figure 1. Cumulative incidence curves for the composite of cardiovascular death or heart failure among patients in the placebo arm of
the Prevention of Events With Angiotensin Converting Enzyme (PEACE) trial (n�1868) categorized by quartiles of midregional pro-atrial
natriuretic peptide (MR-proANP), midregional pro-adrenomedullin (MR-proADM), C-terminal pro-endothelin-1 (CT-proET-1), or copeptin.
P values are for log-rank test for trend across quartiles.
unbiased forward selection algorithm to create a multimarker
model. The only 2 biomarkers to enter and remain in a model
already containing clinical covariates were MR-proANP (adjusted HR, 1.79; 95% confidence interval [CI], 1.41–2.26;
P�0.001) and MR-proADM (adjusted HR, 1.27; 95% CI,
1.07–1.51; P�0.007).
The addition of MR-proANP, MR-proADM, and CTproET-1 individually to the clinical model significantly improved metrics of discrimination (Table 4). In contrast, the
addition of copeptin did not improve these metrics. The addition
We have previously measured NT-proBNP and cTnT in this
population, and the association of those biomarkers with cardiovascular death or heart failure in a model adjusted for the
aforementioned clinical covariates is shown in Table X in the
online-only Data Supplement. Ranking each biomarker individually on the basis of the magnitude of risk (HR) per 1 SD gives
the following order: MR-proANP (1.97), NT-proBNP (1.73),
MR-proADM (1.48), CT-proET-1 (1.47), and cTnT (1.37).
Given the correlation between the biomarkers and that none is
established for routine use in this population, we used an
Table 3.
Multivariable-Adjusted Association of Biomarker Levels and Clinical Outcomes in the Placebo Arm Adjusted for Clinical Factors
Adjusted Risk for CV Death or Heart Failure
Biomarker
HR (95% CI) per 1-SD
Increase in Log-Transformed
Biomarker Values
HR (95% CI) Across Quartiles
P
1
2
3
P
4
Multiple Partial
Trend
MR-proANP
1.97 (1.58 –2.46)
�0.001
Referent
1.60 (0.70 –3.66)
2.72 (1.24 –5.96)
4.35 (1.96 –9.62)
�0.0001
�0.0001
MR-proADM
1.48 (1.27–1.73)
�0.001
Referent
1.90 (0.77–4.69)
2.45 (1.03–5.82)
5.51 (2.38–12.75)
�0.0001
�0.0001
CT-proET-1
1.47 (1.15–1.88)
0.002
Referent
2.03 (1.03–4.04)
0.99 (0.46–2.11)
2.73 (1.41–5.27)
�0.001
0.01
Copeptin
1.10 (0.91–1.33)
0.32
Referent
0.77 (0.37–1.57)
1.11 (0.66–1.86)
1.41 (0.87–2.28)
0.30
0.11
CV indicates cardiovascular; HR, hazard ratio; CI, confidence interval; MR-proANP, midregional pro-atrial natriuretic peptide; MR-proADM, midregional
pro-adrenomedullin; and CT-proET-1, C-terminal pro-endothelin-1. Covariates in the model include standard clinical factors: age, sex, weight, history of hypertension,
history of diabetes mellitus, current tobacco use, prior myocardial infarction, prior percutaneous coronary intervention or coronary artery bypass graft surgery, systolic
blood pressure, estimated glomerular filtration rate, ratio of apolipoprotein B to A, left ventricular ejection fraction, aspirin use, �-blocker use, and lipid-lowering
medication use. Each biomarker was analyzed separately in the placebo arm. In quartile analyses, “multiple partial” refers to a 3-df test for the addition of all quartiles
and “trend” refers to a 1-df test for linear trend across quartiles.
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Sabatine et al
Biomarkers of Cardiovascular Stress in Stable CAD
Table 4. Impact of Biomarker Levels and Metrics of
Discrimination and Reclassification in the Placebo Arm
Integrated
Discrimination
Index
C Statistic
Net
Reclassification
Improvement
Model
Value
P
Value, %
P
Value
P
Clinical model
alone
0.768
N/A
N/A
N/A
N/A
N/A
237
and CT-proET-1 uniformly and significantly improved the C
statistic of multivariable models already containing clinical
covariates, regardless of whether NT-proBNP, cTnT, or both
were also in the model; conversely, adding NT-proBNP and
cTnT to a model containing clinical covariates as well as
MR-proANP, MR-proADM, and CT-proET-1 did not improve
the C statistic (Table XI in the online-only Data Supplement).
Interaction With Trandolapril Therapy
�0.0001 0.412 �0.0001
Clinical model� 0.804 0.0018
MR-proANP
3.8
Clinical model� 0.788 0.0064
MR-proADM
1.9
0.0027 0.362
0.0003
Clinical model� 0.779 0.23
CT-proET-1
1.2
0.047
0.205
0.039
Clinical model� 0.769 0.85
copeptin
0.2
0.14
0.061
0.54
MR-proANP indicates midregional pro-atrial natriuretic peptide; MR-proADM,
midregional pro-adrenomedullin; and CT-proET-1, C-terminal pro-endothelin-1.
Terms in the clinical model include age, sex, weight, history of hypertension, history
of diabetes mellitus, current tobacco use, prior myocardial infarction, prior
percutaneous coronary intervention or coronary artery bypass graft surgery, systolic
blood pressure, estimated glomerular filtration rate, ratio of apolipoprotein B to A,
left ventricular ejection fraction, aspirin use, �-blocker use, and lipid-lowering
medication use. Each biomarker was analyzed separately in the placebo arm. P
values are for comparison with clinical model alone.
of all 3 biomarkers to the clinical model improved the C statistic
from 0.768 to 0.809 and yielded an integrated discrimination
improvement of 4.6% and an net reclassification improvement
of 0.435 (all P�0.0005). Adding MR-proANP, MR-proADM,
In the overall biomarker cohort, treatment with trandolapril
resulted in an HR of 0.80 (95% CI, 0.61–1.05) for cardiovascular
death or heart failure. Notably, however, among patients having
an MR-proANP, MR-proADM, or CT-proET-1 level in the top
quartile and thus at the highest risk of cardiovascular death or
heart failure based on these biomarkers, trandolapril significantly reduced the risk of cardiovascular death or heart failure by
34% to 44%, whereas no benefit was observed among those with
lower levels (Figure 2A). In contrast, there was no significant
benefit from treatment with trandolapril among patients in the
highest quartiles of either NT-proBNP or cTnT (Figure I in the
online-only Data Supplement).
A gradient of benefit (Pinteraction�0.016) with trandolapril
therapy was observed in patients categorized according to
whether they had elevated levels of 0 (n�2037), 1 (n�891), 2
(n�472), or all 3 (n�317) novel biomarkers that we found to be
associated with cardiovascular death or heart failure in adjusted
analyses (Figure 2B). When the results were dichotomized,
among the 2928 patients (79% of the biomarker cohort) with �1
elevated biomarker, there was no benefit of trandolapril therapy
on the risk of cardiovascular death or heart failure (HR, 1.09;
Figure 2. Benefit of trandolapril on the risk of the composite of cardiovascular (CV) death or heart failure in 3717 patients from the Prevention of Events With Angiotensin Converting Enzyme (PEACE) trial categorized according to their levels of biomarkers of cardiovascular stress. A, Patients are categorized according to whether their level of each biomarker of cardiovascular stress was in the top
quartile (quartile 4) or not (quartiles 1–3). The P values for interaction were 0.16, 0.02, 0.09, and 0.72 for midregional pro-atrial natriuretic peptide (MR-proANP), midregional pro-adrenomedullin (MR-proADM), C-terminal pro-endothelin-1 (CT-proET-1), and copeptin,
respectively. B, Patients are categorized by the number of biomarkers (MR-proANP, MR-proADM, and CT-proET-1) in the top quartile;
the P value for interaction is 0.016. In A and B, the diamonds indicate the effect in the entire biomarker cohort, with the center indicating the point estimate and the left and right ends indicating the 95% confidence interval (CI). The squares and circles indicate the point
estimate, and the horizontal lines indicate the 95% CIs for the effect in each subgroup. HR indicates hazard ratio.
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Circulation
January 17, 2012
Figure 3. Cumulative incidence curves for
the composite of cardiovascular death or
heart failure in 3717 patients from the Prevention of Events with Angiotensin Converting Enzyme (PEACE) trial categorized by
whether they had �1 elevated biomarkers
(solid lines; red indicates 1487 patients
treated with placebo; blue, 1441 patients
treated with trandolapril) or �2 elevated
biomarkers (dashed lines; red indicates 381
patients treated with placebo; blue, 408
patients treated with trandolapril). HR indicates hazard ratio; CI, confidence interval.
95% CI, 0.74 –1.59), whereas among the 789 patients (21% of
the biomarker cohort) with �2 elevated biomarkers, trandolapril
significantly reduced the rate of cardiovascular death or
heart failure (HR, 0.53; 95% CI, 0.36 – 0.80; P�0.002,
Pinteraction�0.012; Figure 3). The absolute risk reduction over 6
years in this latter group was 7.5%; thus, in this subset, 14 patients
would need to be treated with trandolapril for 6 years to prevent a
cardiovascular death or hospitalization for heart failure.
Discussion
In an exploratory analysis among a large cohort of patients
with stable CAD and preserved LVEF, we have demonstrated
that elevated levels of 3 novel biomarkers of cardiovascular
stress are independently associated with the subsequent risk
of cardiovascular death and heart failure. Specifically, MRproANP, MR-proADM, and CT-proET-1 were associated
with cardiovascular death or heart failure independently of
clinical factors, renal function, and LVEF, ranging from 47%
higher risk to a near doubling of the risk per each 1-SD
increase in log-transformed biomarker levels and almost 3
times to �5 times the risk for patients in the highest
compared with the lowest quartile. In contrast, a fourth
biomarker, copeptin, was not independently associated with
the risk of cardiovascular events. Moreover, and in contrast to
previous results with other biomarkers, including NTproBNP and cTnT,6,26,31 elevated levels of these 3 biomarkers
identified patients in whom, despite appearing to be at low
risk clinically, therapy with an ACE inhibitor resulted in a
significant reduction in the risk of cardiovascular death or
heart failure.
We used assays for the prohormones ANP, ADM, and ET-1
because the prohormones are released in an equimolar ratio to
the vasoactive hormones but have a longer half-life. When
possible, we also used assays for a midregional fragment
because these fragments are more stable in vivo and ex vivo than
the amino- or carboxy-terminal part of the prohormone, thereby
minimizing the risk of underestimation of levels as a result of
early degradation of crucial epitopes at the extreme ends of the
molecule.32 In studies of patients with established heart failure,
elevated levels of MR-proANP, MR-proADM, and CT-proET-1
have been shown to be associated with mortality independently
of clinical variables, and the biomarkers have displayed prognostic and discriminatory value that has compared favorably
with BNP and/or NT-proBNP.13–15
Concordant with those observations, in our data set, we found
that during the creation of a multimarker model adjusted for
clinical factors, MR-proANP and MR-proADM proved to be the
strongest 2 biomarkers, superior to NT-proBNP and cTnT
measured with a highly sensitive assay. Because this was a
clinical rather than a mechanistic study, we can only speculate as
to the reasons for the superior performance, which could be
related to subtle differences in the respective pathobiology
underlying elevation of each of the biomarkers or could stem
from more favorable analytic properties that translate into a
better reflection of subclinical cardiovascular pathology. Regardless, our data are supported by and extend previous findings
regarding these biomarkers and atherosclerosis reported by
Schnabel and colleagues7 in several ways, including studying
patients who were free of heart failure at baseline and whose
LVEF was known and incorporated into all multivariable models, using patients enrolled from a much broader number of
clinical centers, and examining the specific clinical events that
biomarkers of cardiac stress are best suited to predict, namely
cardiovascular death and heart failure, rather than a composite of
death or MI.
Critically, whereas other biomarker analyses have been embedded in observational cohorts, we had the benefit of studying
these biomarkers in a randomized clinical trial, allowing us to
examine the interaction between baseline biomarker levels and
the efficacy of the randomized therapy without concern for the
inherent bias in examining nonrandomly allocated therapies.
Using a panel of these novel biomarkers of cardiovascular stress,
we were able to identify approximately one fifth of enrolled
patients with stable CAD in whom ACE inhibitor therapy nearly
halved the risk of cardiovascular death or heart failure. Our
findings are conceptually analogous to the results of Richards
and colleagues,33,34 who showed that elevated levels of biomarkers of cardiovascular stress identified patients with ischemic left
ventricular dysfunction who benefited from �-blockade.
Current practice guidelines for the management of patients
with stable CAD recommend ACE inhibitor therapy in those
patients with an LVEF �40%; in addition, in part on the basis of
data from the Heart Outcomes Prevention Evaluation (HOPE)
trial, ACE inhibitors are recommended for patients who are
relatively high risk and/or have another compelling clinical
indication (eg, hypertension, diabetes mellitus, or chronic kidney
disease).35 In contrast, for lower-risk patients like those in the
PEACE trial, in which the event rate in the placebo arm was
lower than the event rate in the ACE inhibitor arm from the
HOPE trial, the guidelines note that it is reasonable but not
recommended to use ACE inhibitors when cardiovascular risk
factors are well controlled and revascularization has been performed. Our data now support the hypothesis that within this
very large population of patients who appear to be of lower risk
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Biomarkers of Cardiovascular Stress in Stable CAD
clinically, biomarkers of cardiovascular stress levels may be
useful to help guide such decision making. Although additional
prospective analyses will need to be done if these biomarkers
become available for routine clinical use in the United States,
targeting long-term drug therapy based on a panel of biomarkers
should be cost effective.
Several potential limitations of our study deserve consideration. The PEACE clinical trial population, which was predominantly a white, male population �50 years of age, is not
representative of the general population. However, the clinical
and laboratory characteristics of patients in this study are typical
of patients with stable coronary disease, and a high proportion of
patients were treated with �-blockers and lipid-lowering therapy.
Blood samples were obtained from only a subgroup of the
participants in the overall PEACE trial, but there were no
clinically relevant differences between patients who did and did
not participate in the biomarker substudy. Banked biosamples
were used, but any sample degradation should be random with
respect to cardiovascular outcomes, and thus any resultant
misclassification should only bias toward the null hypothesis.
The formation of the multimarker score for interaction with
therapy should be considered exploratory, and the optimal
combination of biomarkers and their cut points merits validation
in additional populations. Heart failure events were not a
component of the prespecified primary outcome in the original
trial design but are a well-established outcome predicted by
biomarkers of cardiac stress and prevented by ACE inhibitors in
other populations.6,19,20,26
Conclusion
In apparently low-risk patients with stable CAD and preserved LVEF, elevated levels of novel biomarkers reflecting
cardiovascular stress may be useful both to identify patients
who are at higher risk of cardiovascular death and heart
failure and to select patients who derive a significant benefit
from ACE inhibitor therapy.
Sources of Funding
The PEACE trial was supported by a contract from the National
Heart, Lung, and Blood Institute (NHLBI; N01 HC65149) and by
Knoll Pharmaceuticals and Abbott Laboratories, which also provided
the study medication. Dr Sabatine was supported in part by grant
R01 HL094390 from the NHLBI. Reagent for measurement of
MR-proANP, MR-proADM, CT-proET-1, and copeptin were provided by B.R.A.H.M.S. GmbH (Henningsdorf, Germany). The
NHLBI, Knoll Pharmaceuticals, Abbott Laboratories, and
B.R.A.H.M.S. GmbH had no role in the design and conduct of the
study; collection, management, analysis, and interpretation of the
data; or preparation, review, or approval of the manuscript.
Disclosures
Drs Sabatine, Morrow, and Braunwald and S. Sloan are members of the
TIMI Study Group, which has received research grant support from
Accumetrics, Amgen, AstraZeneca, Beckman Coulter, BG Medicine,
B.R.A.H.M.S. GmbH, Bristol-Myers Squibb, CV Therapeutics, Daiichi
Sankyo Co Ltd, diaDexus, Eli Lilly and Co, Genentech, GlaxoSmithKline, Integrated Therapeutics, Johnson & Johnson, Merck and Co,
Nanosphere, Novartis Pharmaceuticals, Nuvelo, Ortho-Clinical Diagnostics, Pfizer, Roche Diagnostics, Sanofi-aventis, Siemens, and Singulex. Dr Sabatine reports receiving honoraria for educational presentations from Bristol-Myers Squibb and diaDexus, as well as
remuneration for consulting from AstraZeneca, Bristol-Myers Squibb/
Sanofi-aventis Joint Venture, Daiichi-Sankyo/Lilly Partnership, Sanofi-
239
aventis, and Singulex. Dr Morrow reports receiving honoraria for
educational presentations from Eli Lilly; remuneration for consulting
from Beckman-Coulter, Boehringer Ingelheim, Cardiokinetix, Critical
Diagnostics, Gilead, Instrumentation Laboratory, Ikaria, Menarini,
Merck, OrthoClinical Diagnostics, Servier, Roche Diagnostics, and
Siemens; and remuneration from AstraZeneca for adjudication as a
member of a Clinical Events Committee. Dr de Lemos reports receiving
grant support from Roche and Alere, Inc (formerly Biosite) and
consulting income from Alere, Johnson & Johnson Roche Diagnostics,
and Tethys Biomedical. Dr Omland reports receiving speakers’ honoraria from Roche Diagnostics and Abbott Laboratories. Dr Jarolim
reports receiving research support from Amgen, Beckman-Coulter,
Ortho Clinical Diagnostics, Roche Diagnostics, and Siemens Healthcare
Diagnostics; honoraria for educational presentations from Ortho Clinical
Diagnostics; and consulting fees from T2 Biosystems. Dr Pfeffer reports
receiving grant support from Amgen, Novartis, and Sanofi-aventis, as
well as consulting fees from Amgen, Anthera, Boehringer Ingelheim,
Boston Scientific, Bristol-Myers Squibb, Cerenis, Eleven Biotherapeutics, GlaxoSmithKline, Hamilton Health Sciences, Karo Bio, Novartis,
Roche, Salutria, Sanofi Aventis, Servier, and University of Oxford. Dr
Pfeffer is a coinventor on a patent that Brigham and Women’s Hospital
has for the use of inhibitors of the renin-angiotensin system in selected
survivors of MI. His share of the licensing agreements with Novartis and
Boehringer, which are irrevocably transferred to charity, are not linked
to sales. Dr Braunwald reports receiving remuneration for symposia
and/or consulting from Amorcyte, CardioRentis, CVRx, Daiichi Sankyo, Eli Lilly, Genzyme, Medicines Co, and Merck & Co. The other
authors report no conflicts.
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artery disease. N Engl J Med. 2009;361:2538 –2547.
27. Guilford JP. Fundamental Statistics in Psychology and Education. New
York, NY: McGraw Hill; 1956.
28. Pencina MJ, D’Agostino RB Sr, D’Agostino RB Jr, Vasan RS. Evaluating
the added predictive ability of a new marker: from area under the ROC
curve to reclassification and beyond. Stat Med. 2008;27:157–172.
29. Harrell FE. Harrell Miscellaneous. R Graphical Manual. December 26,
2008. http://biostat.mc.vanderbilt.edu/s/Hmisc. 2009. Accessed
December 16, 2010.
30. Pencina MJ, D’Agostino RB Sr, Steyerberg EW. Extensions of net reclassification improvement calculations to measure usefulness of new biomarkers. Stat Med. 2011;30:11–21.
31. Sabatine MS, Morrow DA, Jablonski KA, Rice MM, Warnica JW,
Domanski MJ, Hsia J, Gersh BJ, Rifai N, Ridker PM, Pfeffer MA,
Braunwald E. Prognostic significance of the Centers for Disease Control/
American Heart Association high-sensitivity C-reactive protein cut points
for cardiovascular and other outcomes in patients with stable coronary
artery disease. Circulation. 2007;115:1528 –1536.
32. Ala-Kopsala M, Magga J, Peuhkurinen K, Leipala J, Ruskoaho H, Leppaluoto J, Vuolteenaho O. Molecular heterogeneity has a major impact on
the measurement of circulating N-terminal fragments of A- and B-type
natriuretic peptides. Clin Chem. 2004;50:1576 –1588.
33. Richards AM, Doughty R, Nicholls MG, Macmahon S, Ikram H, Sharpe
N, Espiner EA, Frampton C, Yandle TG. Neurohumoral prediction of
benefit from carvedilol in ischemic left ventricular dysfunction:
Australia-New Zealand Heart Failure Group. Circulation. 1999;99:
786 –792.
34. Richards AM, Doughty R, Nicholls MG, MacMahon S, Sharpe N,
Murphy J, Espiner EA, Frampton C, Yandle TG. Plasma N-terminal
pro-brain natriuretic peptide and adrenomedullin: prognostic utility and
prediction of benefit from carvedilol in chronic ischemic left ventricular
dysfunction: Australia-New Zealand Heart Failure Group. J Am Coll
Cardiol. 2001;37:1781–1787.
35. Fraker TD Jr, Fihn SD, Gibbons RJ, Abrams J, Chatterjee K, Daley J,
Deedwania PC, Douglas JS, Ferguson TB Jr, Fihn SD, Fraker TD Jr,
Gardin JM, O’Rourke RA, Williams SV, Smith SC Jr, Jacobs AK, Adams
CD, Anderson JL, Buller CE, Creager MA, Ettinger SM, Halperin JL,
Hunt SA, Krumholz HM, Kushner FG, Lytle BW, Nishimura R, Page RL,
Riegel B, Tarkington LG, Yancy CW. 2007 Chronic angina focused
update of the ACC/AHA 2002 guidelines for the management of patients
with chronic stable angina: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines
Writing Group to develop the focused update of the 2002 guidelines for
the management of patients with chronic stable angina. Circulation.
2007;116:2762–2772.
CLINICAL PERSPECTIVE
The benefit of angiotensin-converting enzyme inhibitors in low-risk patients with stable coronary artery disease without heart
failure remains controversial, and current practice guidelines note that it is reasonable but not recommended to use
angiotensin-converting enzyme inhibitors when cardiovascular risk factors are well controlled and revascularization has been
performed. We now demonstrate that elevated levels of 3 novel biomarkers of cardiovascular stress, midregional pro-atrial
natriuretic peptide, midregional pro-adrenomedullin, and C-terminal pro-endothelin-1, are associated with the subsequent risk of
cardiovascular death and heart failure independently of clinical factors (adjusted hazard ratios per 1-SD increase of 1.97, 1.48,
and 1.47, respectively; P�0.002 for each biomarker). Furthermore, elevated levels of these biomarkers identified patients in
whom therapy with an angiotensin-converting enzyme inhibitor resulted in a significant reduction in the risk of cardiovascular
death or heart failure. Specifically, trandolapril significantly reduced the risk of cardiovascular death or heart failure in patients
who had elevated levels of �2 biomarkers (hazard ratio, 0.53; 95% confidence interval, 0.36–0.80), whereas there was no benefit
in patients with elevated levels of 0 or 1 biomarker (hazard ratio, 1.09; 95% confidence interval, 0.74–1.59; Pinteraction�0.012).
Thus, in patients with stable coronary artery disease and preserved left ventricular ejection fraction, elevated levels of novel
biomarkers of cardiovascular stress identify patients who are at higher risk of cardiovascular death and heart failure and may be
useful to select patients who derive significant benefit from angiotensin-converting enzyme inhibitor therapy.
Downloaded from http://circ.ahajournals.org/ by IMED Korea on April 23, 2012
Page 315
Maladie coronaire
Intérêt des différents biomarqueurs du stress cardiovasculaire
pour la prédiction du risque et l’orientation du traitement
médical chez les patients coronariens stables
Marc S. Sabatine, MD, MPH ; David A. Morrow, MD, MPH ; James A. de Lemos, MD ;
Torbjorn Omland, MD, PhD ; Sarah Sloan, MS ; Petr Jarolim, MD, PhD ;
Scott D. Solomon, MD ; Marc A. Pfeffer, MD, PhD ; Eugene Braunwald, MD
Contexte—Les biomarqueurs circulants peuvent renseigner sur le degré de stress cardiovasculaire infraclinique et,
par là-même, faciliter la stratification des risques et l’adaptation du traitement.
Méthodes et résultats—Nous avons mesuré les taux plasmatiques de quatre biomarqueurs cardiovasculaires, à savoir les
fragments médians du propeptide natriurétique atrial (MR-proANP) et de la pro-adrénomédulline (MR-proADM), le
fragment C-terminal de la pro-endothéline de type 1 (CT-proET-1) et la copeptine, chez 3 717 patients coronariens
stables dont la fraction d’éjection ventriculaire gauche était conservée et qui avaient été randomisés en vue de recevoir du
trandolapril ou un placebo dans le cadre de l’essai Prevention of Events With Angiotensin Converting Enzyme
(PEACE). Après ajustement en fonction des facteurs cliniques de risque cardiovasculaire et de la fraction d’éjection
ventriculaire gauche, des taux augmentés de MR-proANP, de MR-proADM et de CT-proET-1 se sont révélés corrélés
de façon indépendante avec le risque de décès de cause cardiovasculaire ou de survenue d’une insuffisance
cardiaque (risques relatifs pour chaque augmentation de 1 ET des logarithmes naturels des taux de ces biomarqueurs
respectivement estimés à 1,97, 1,48 et 1,47 ; p ≤0,002 pour chaque biomarqueur). Ces trois biomarqueurs ont également
significativement amélioré le pouvoir de discrimination du modèle clinique auquel ils avaient été incorporés.
L’administration de trandolapril a significativement abaissé le risque de décès de cause cardiovasculaire ou d’insuffisance
cardiaque chez les patients qui présentaient des élévations des taux d’au moins deux biomarqueurs (risque relatif : 0,53 ;
intervalle de confiance [IC] à 95 % : 0,36 à 0,80), alors qu’elle n’a eu aucune influence bénéfique en l’absence d’élévation
des biomarqueurs ou lorsque le taux d’un seul d’entre eux était augmenté (risque relatif : 1,09 ; IC à 95 % : 0,74 à 1,59 ;
pinteraction = 0,012).
Conclusions—Nos observations tendent à montrer que, chez les patients présentant une maladie coronaire stable et une
fraction d’éjection ventriculaire gauche préservée, la mise en évidence de taux augmentés de ces nouveaux biomarqueurs
du stress cardiovasculaire peut permettre de dépister ceux d’entre eux qui encourent un risque plus élevé de décès de
cause cardiovasculaire ou d’insuffisance cardiaque et, par ailleurs, d’identifier les sujets chez lesquels la prescription d’un
inhibiteur de l’enzyme de conversion de l’angiotensine serait hautement bénéfique. (Traduit de l’anglais : Evaluation
of Multiple Biomarkers of Cardiovascular Stress for Risk Prediction and Guiding Medical Therapy in Patients With
Stable Coronary Disease. Circulation. 2012;125:233–240.)
Mots clés : inhibiteurs de l’enzyme de conversion de l’angiotensine 䊏 biomarqueurs 䊏 maladie coronaire
’élévation des taux de biomarqueurs circulants découlant
de l’augmentation de la précharge ou de la postcharge
cardiaque témoigne de l’existence d’un stress cardiovasculaire
infraclinique et pourrait, dès lors, constituer un élément
susceptible de faciliter la stratification des risques.1 De fait, il
a été démontré que l’augmentation du taux de peptide
L
Reçu le 24 août 2011 ; accepté le 7 décembre 2011.
Groupe d’étude TIMI, Unité Cardiovasculaire, Brigham and Women’s Hospital et Service de Médecine, Faculté de Médecine d’Harvard, Boston,
Massachusetts, Etats-Unis (M.S.S., D.A.M., S.S., E.B.) ; Service de Cardiologie, Southwestern Medical Center de l’Université du Texas, Dallas, Etats-Unis
(J.A.d.L.) ; Service de Médecine de l’Hôpital Universitaire d’Akershus, Centre de Recherche sur l’Insuffisance Cardiaque et Centre de Recherche
Cardiologique KG Jebsen, Université d’Oslo, Oslo, Norvège (T.O.) ; Service d’Anatomopathologie, Brigham and Women’s Hospital, Faculté de Médecine
d’Harvard, Boston, Massachusetts, Etats-Unis (P.J.) ; et Unité Cardiovasculaire, Brigham and Women’s Hospital, Faculté de Médecine d’Harvard, Boston,
Massachusetts, Etats-Unis (S.D.S., M.A.P.).
Le rédacteur invité pour cet article était le Dr Gregg C. Fonarow.
Le supplément de données uniquement disponible en ligne peut être consulté, tout comme la version anglaise de cet article, sur le site :
http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.111.063842/-/DC1.
Correspondance : Marc S. Sabatine, MD, MPH, TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital, 350 Longwood Ave,
Boston, MA 02115, Etats-Unis. E-mail : [email protected]
© 2012 American Heart Association, Inc.
Circulation est disponible sur le site : http://circ.ahajournals.org
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natriurétique de type B (BNP ; l’observation valant pour
l’hormone elle-même et pour le fragment amino-terminal
de son précurseur [NT-proBNP]) est prédictive de décès
et/ou d’insuffisance cardiaque chez de multiples catégories
d’individus, depuis la population générale jusqu’aux patients
atteints d’insuffisance cardiaque avérée.1–7
Le développement de méthodes de dosage innovantes
ayant pour cibles les épitopes plus stables des hormones et
prohormones qui sont libérées en réponse aux agressions dont
sont l’objet les cardiomyocytes et/ou l’appareil vasculaire est
de nature à permettre une évaluation plus fine des risques.
Plus précisément, le peptide natriurétique atrial (ANP) est une
substance vasodilatatrice et natriurétique qui est synthétisée
par le myocarde lorsque la tension pariétale augmente.8
L’adrénomédulline (ADM) est un puissant vasodilatateur
produit par la médullaire des surrénales, les cellules de
l’endothélium vasculaire, le cœur et d’autres structures sous
l’effet de l’étirement physique et de certaines cytokines, sa
concentration cardiaque s’élevant en cas d’augmentation de
la précharge ou de la postcharge.9,10 L’endothéline de type 1
(ET-1) est à la fois un puissant vasoconstricteur et une
hormone profibrotique qui est sécrétée par les cellules de
l’endothélium vasculaire et dont le taux augmente parallèlement aux forces de cisaillement et à la pression artérielle
pulmonaire.11 La copeptine est un peptide stable issu du
précurseur de l’arginine-vasopressine, un vasoconstricteur
sécrété par la post-hypophyse en réponse à la fois aux stimuli
osmotiques et aux modifications hémodynamiques détectées
par les barorécepteurs cardiaques et vasculaires.12 Il a été
établi que, chez les patients atteints d’insuffisance cardiaque
avérée, l’élévation des taux de ces marqueurs biologiques est
corrélée avec l’augmentation du risque de décès et/ou
d’événement lié à l’insuffisance cardiaque.13–16 Le fait que le
dosage de ces quatre biomarqueurs du stress cardiovasculaire
soit désormais réalisable par des méthodes d’analyse dont
l’apport potentiel a été démontré chez les patients en question
a tout naturellement conduit à examiner leur utilité dans une
population plus vaste.
Les inhibiteurs de l’enzyme de conversion de l’angiotensine
(IEC) réduisent significativement le risque de décès et
d’événements liés à l’insuffisance cardiaque chez les patients
atteints d’une telle affection, leur impact bénéfique étant
maximal dans les formes cliniques les plus sévères.17 Chez les
patients présentant un infarctus du myocarde (IDM) en phase
aiguë, les IEC exercent leur effet bénéfique le plus marqué
lorsque l’IDM présente des caractéristiques cliniques à haut
risque telles qu’une localisation à la paroi antérieure ou une
altération de la fonction systolique ventriculaire gauche.18
En revanche, les données sont moins tranchées en ce qui
concerne le rôle joué par ces médicaments chez les patients
coronariens stables exposés à un risque plus faible car
indemnes d’insuffisance cardiaque.19–21 Les hypothèses que
nous avons donc cherché à vérifier étaient, d’une part, que,
chez ces patients, l’élévation des taux de fragments médians
du pro-ANP (MR-proANP), de la proADM, de fragment
C-terminal de la proET-1 (CT-proET-1) et de copeptine serait
prédictive de décès de cause cardiovasculaire et d’insuffisance
cardiaque indépendamment des facteurs de risque cliniques
et, d’autre part, que le dosage de ces biomarqueurs
10:00:26:07:12
Page 316
permettrait d’identifier les patients susceptibles de tirer un
meilleur bénéfice clinique de la prescription d’un IEC. Nous
avons testé ces hypothèses en mesurant les taux plasmatiques
de ces nouveaux biomarqueurs du stress cardiovasculaire
chez 3 717 patients coronariens stables dont la fraction
d’éjection ventriculaire gauche (FEVG) était conservée, qui
ont été randomisés en vue de recevoir du trandolapril ou
un placebo dans le cadre de l’essai PEACE (Prevention of
Events With Angiotensin Converting Enzyme [prévention des
événements par l’administration d’un enzyme de conversion
de l’angiotensine]).
Méthodes
Population de l’étude
L’étude a porté sur 3 717 patients atteints d’une maladie coronaire
stable documentée qui avaient été inclus dans l’essai PEACE
(www.ClinicalTrials.gov ; identifiant unique : NCT00000558) et chez
lesquels un échantillon sanguin avait été prélevé à leur entrée dans
l’essai. Le plan d’organisation et les principaux résultats de PEACE
ont été précédemment publiés,21 les aspects majeurs étant détaillées au
chapitre « Méthodes » et dans le Tableau I du supplément de données
uniquement disponible en ligne. En résumé, les patients n’étaient
pas insuffisants cardiaques à leur entrée dans l’étude et aucun
n’avait été hospitalisé pour un syndrome coronaire aigu ni n’avait fait
l’objet d’une intervention de revascularisation coronaire dans les
3 mois ayant précédé son inclusion. L’étude mère et la présente
sous-étude ont toutes deux été approuvées par les comités d’éthique
des établissements concernés et tous les patients ont fourni leur
consentement éclairé.
Analyse des marqueurs biologiques
Les taux plasmatiques initiaux de MR-proANP,22 MR-proADM,23
CT-proET-124 et copeptine (coffrets de dosage B.R.A.H.M.S. Gmbh,
Henningsdorf, Allemagne) ont été mesurés dans le laboratoire des
essais cliniques TIMI (Thrombolysis in Myocardial Infarction
[thrombolyse dans l’infarctus du myocarde]) (Boston, Massachusetts,
Etats-Unis) comme décrit au chapitre « Méthodes » et dans le Tableau
II du supplément de données uniquement disponible en ligne.
Les taux de NT-proBNP et de troponine T cardiaque (TnTc)
avaient également été mesurés chez ces patients à l’entrée dans l’essai
par une méthode de dosage hautement sensible, comme cela a été
précédemment publié et est résumé au chapitre « Méthodes » du
supplément de données uniquement disponible en ligne.6,26 Les
dosages ont tous été réalisés par du personnel qui ignorait les résultats
cliniques et le traitement assigné aux patients.
Critères de jugement
En nous fondant sur les données ayant établi la valeur prédictive
des biomarqueurs du stress cardiovasculaire,6 nous avons retenu
comme critère de jugement principal de l’étude l’incidence de
l’événement composite regroupant le décès de cause cardiovasculaire
et l’hospitalisation pour insuffisance cardiaque. Nous avons
également examiné d’autres événements cardiovasculaires majeurs
qui avaient été pris en compte chez les patients de l’étude, à savoir le
décès lié à toute cause, l’IDM aigu, l’accident vasculaire cérébral en
phase aiguë et les procédures de revascularisation coronaire (par
approche percutanée ou chirurgicale). Les modalités de validation des
événements sont détaillées au chapitre « Méthodes » du supplément
de données uniquement disponible en ligne. Tous les événements
cliniques ont été qualifiés préalablement au dosage des marqueurs
biologiques.
Analyses statistiques
Les caractéristiques initiales sont décrites sous forme de moyennes
± ET dans le cas de variables continues de distribution normale et de
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Sabatine et al
Biomarqueurs du stress cardiovasculaire dans la maladie coronaire stable
nombres et pourcentages dans le cas de variables catégorielles. Un test
de sommation des rangs de Wilcoxon et un test du χ 2 pour la tendance
ont été employés pour analyser les différences de valeurs des variables
continues et catégorielles relevées à l’entrée dans l’étude en fonction
des quartiles des taux de biomarqueurs. Nous avons eu recours à la
méthode de corrélation de Spearman pour rechercher les liens
existant entre les différents biomarqueurs en effectuant un classement
en fonction des valeurs seuils standardisées.27 Un test des rangs
logarithmiques a été effectué pour comparer les incidences cumulées
d’événements cliniques entre les quartiles de taux de chaque
marqueur biologique. Des modèles à risques proportionnels de Cox
ont été utilisés pour analyser les relations entre les taux de biomarqueurs et les événements cliniques. Dans les modèles en question,
les taux de biomarqueurs ont été examinés à la fois en tant que
variables continues (après transformation en leur logarithme naturel)
et en tant que variables catégorielles classées par quartile. Les liens
observés ont été ajustés pour l’âge, le sexe, le poids corporel,
l’hypertension artérielle, le diabète, l’existence d’un tabagisme,
les antécédents d’IDM et d’intervention coronaire percutanée ou
de pontage aorto-coronaire, la pression artérielle systolique, le
taux de filtration glomérulaire estimé, le rapport apolipoprotéine
B/apolipoprotéine A, la FEVG et les prescriptions d’aspirine, de
bêtabloquants et d’hypolipémiants. En commençant par un modèle
qui regroupait toutes les covariables cliniques mentionnées ci-dessus,
nous avons employé un algorithme de sélection par éliminations
successives (dans lequel le degré de significativité des variables devait
atteindre une valeur de p inférieure à 0,05 pour que celles-ci puissent
être conservées dans le modèle) pour départager les quatre biomarqueurs nouvellement validés, auxquels ont été ajoutés le
NT-proBNP et la TnTc. L’augmentation du pouvoir prédictif conféré
par l’inclusion de ces biomarqueurs, par rapport à la valeur informative des facteurs cliniques, a été également évaluée en examinant
les modifications qui en avaient résulté en termes de statistique C,
d’amélioration de la discrimination intégrée et d’amélioration de la
reclassification nette indépendante de la catégorie (pour de plus
amples détails, se reporter au chapitre « Méthodes » du supplément de
données uniquement disponible en ligne).28–30
Pour juger de l’hétérogénéité de l’effet du trandolapril sur le risque
de décès de cause cardiovasculaire ou d’insuffisance cardiaque, les
risques relatifs (RR) ont été calculés selon que les patients se situaient
ou non dans la catégorie de risque la plus élevée, c’est-à-dire dans le
plus haut quartile de taux de l’un des biomarqueurs considérés. Pour
rechercher une éventuelle modification statistiquement significative de
l’effet exercé, nous avons conçu un modèle à risques proportionnels
de Cox qui prenait en compte l’administration de trandolapril, la
catégorie de risque définie par le taux de biomarqueur et l’interaction
entre les deux.
Les valeurs de p inférieures à 0,05 ont été considérées comme
statistiquement significatives, les tests effectués ayant tous été
bidirectionnels. Aucun ajustement n’a été pratiqué pour les
comparaisons multiples. Bien qu’elles aient été fondées sur de
précédents travaux menés sur ces marqueurs biologiques dans
d’autres populations, toutes les analyses que nous avons effectuées
dans cette sous-étude avaient par essence un caractère exploratoire.
Les analyses ont été réalisées au moyen des programmes STATA/IC
version 10.1 (STATA Corp., College Station, Texas, Etats-Unis) et
R version 2.12.1.
Résultats
Caractéristiques des patients et taux de
biomarqueurs à l’entrée dans l’étude
Les valeurs des quatre biomarqueurs biologiques avaient été
mesurées chez 3 717 patients de l’essai PEACE à leur entrée
dans ce dernier. Les caractéristiques cliniques des patients
sont résumées dans le Tableau 1. Aux termes du protocole, les
patients étaient tous des coronariens stables dont la FEVG
était conservée à une valeur moyenne (± ET) de 58,7 ± 9,6 %.
10:00:26:07:12
Page 317
Tableau 1.
l’étude
317
Caractéristiques des patients à leur entrée dans
Les taux médians de MR-proANP, MR-proADM,
CT-proET-1 et copeptine mesurés à l’entrée dans l’essai
PEACE étaient respectivement de 90,45 pmol/l (25ème–75ème
percentiles : 63,68–128,3 pmol/l), 0,53 nmol/l (25ème–75ème
percentiles : 0,45–0,64 nmol/l), 47,82 pmol/l (25ème–75ème
percentiles : 39,04–57,02 pmol/l) et 6,47 pmol/l (25ème–75ème
percentiles : 0–10,67 pmol/l). Les taux tendaient à être
supérieurs à ceux observés chez le sujet sain, mais, exception
faite du taux de MR-proADM, la majorité des valeurs se
situait en dessous du 97,5ème percentile rapporté dans les
populations en bonne santé et en dessous des taux mesurés
chez les patients atteints d’insuffisance cardiaque avérée
(Tableau II du supplément de données uniquement disponible
en ligne). Les caractéristiques des patients en fonction des
quartiles de taux des marqueurs biologiques sont présentées
dans les Tableaux III à VI du supplément de données
uniquement disponible en ligne. De façon générale, l’élévation
des taux de biomarqueurs du stress cardiovasculaire a été
proportionnelle à l’âge, à la prévalence de l’hypertension
artérielle et à l’altération du taux de filtration glomérulaire
estimé. La FEVG s’est révélée inversement proportionnelle
aux taux de MR-proANP et de copeptine, mais les différences
absolues relevées entre les quartiles supérieur et inférieur
de chacun de ces deux biomarqueurs n’ont été que de,
respectivement, 2,0 et 1,0 %. Parmi les quatre marqueurs,
seuls le MR-proADM et le CT-proET-1 ont présenté une
corrélation relativement forte (r = 0,63) ; pour les deux autres,
les corrélations ont été modérées à faibles (r ≤0,44 ; Tableau VII
du supplément de données uniquement disponible en ligne).
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Septembre 2012
Comme on pouvait s’y attendre, une puissante corrélation
positive a été objectivée entre les taux de MR-proANP et de
NT-proBNP (r = 0,76) ; en revanche, les liens qui unissaient le
NT-proBNP et la TnTc aux autres marqueurs se sont révélés
faibles (r ≤0,38 ; Tableau VII du supplément de données
uniquement disponible en ligne).
Evénements cibles cliniques
Chez les patients de l’essai PEACE qui avaient reçu le placebo,
les taux initiaux de chacun des quatre biomarqueurs du stress
cardiovasculaire se sont montrés étroitement corrélés avec le
risque de décès de cause cardiovasculaire ou d’insuffisance
cardiaque (l’événement composite étant survenu chez 114
patients), chaque élévation de 1 ET du logarithme naturel des
taux de marqueurs s’étant traduite par un quasi-doublement
du risque (p ≤0,002 pour chaque marqueur biologique ;
Tableau 2). Le risque a augmenté avec les quartiles, son niveau
étant apparu particulièrement élevé pour le quatrième d’entre
eux (Figure 1). Des liens similaires ont été relevés entre les
taux de marqueurs biologiques et les risques spécifiques de
décès de cause cardiovasculaire (survenu chez 67 patients) et
d’insuffisance cardiaque (observée chez 56 patients ; Tableau
VIII du supplément de données uniquement disponible en
ligne).
Après ajustement pour les facteurs de risque classiques,
le taux de filtration glomérulaire attendu et la FEVG (se
reporter à la rubrique « Méthodes » pour une description
détaillée des covariables), l’élévation des taux de MRproANP, MR-proADM et CT-proET-1 est demeurée
significativement corrélée avec l’augmentation du risque de
décès de cause cardiovasculaire ou d’insuffisance cardiaque,
chaque élévation de 1 ET du logarithme naturel des taux de
ces marqueurs ayant entraîné des augmentations du risque
allant de 47 % à un taux près de deux fois supérieur (p ≤0,002
pour chaque marqueur biologique) ; dans l’analyse par
quartile, le risque maximal a été observé chez les patients dont
les taux se situaient dans le quartile le plus élevé ; les niveaux
de risque ont, en effet, excédé de près du triple à plus de 5 fois
ceux constatés chez les patients classés dans le quartile le plus
faible. Toutefois, après ajustement multivarié, le lien relevé
avec le taux de copeptine a perdu sa significativité (Tableau 3).
Les mêmes corrélations que celles mises en évidence par les
Tableau 2.
10:00:26:07:12
analyses non ajustées ont été observées entre les taux de
biomarqueurs et les risques spécifiques de décès de cause
cardiovasculaire et d’insuffisance cardiaque (Tableau VIII du
supplément de données uniquement disponible en ligne).
Comparativement à ceux relevés avec le décès de cause
cardiovasculaire, les liens observés avec le décès lié à une
quelconque cause, événement cible ayant une moindre spécificité cardiovasculaire, ont été significatifs mais plus faibles
(Tableau IX du supplément de données uniquement
disponible en ligne). Comme le laissaient prévoir de
précédents travaux,6,26 les corrélations ajustées relevées entre
les taux de ces nouveaux marqueurs biologiques du stress
cardiovasculaire et les risques d’IDM aigu, d’accident
vasculaire cérébral et de revascularisation coronaire se sont
révélées non significatives, exception faite du lien entre le taux
de MR-proANP et l’accident vasculaire cérébral (p = 0,043 ;
Tableau IX du supplément de données uniquement disponible
en ligne).
Nous avions précédemment mesuré les taux de NT-proBNP
et de TnTc dans cette même population ; le Tableau X du
supplément de données uniquement disponible en ligne
montre les liens mis en évidence entre ces biomarqueurs et le
risque de décès de cause cardiovasculaire ou d’insuffisance
cardiaque en employant un modèle ajusté pour les covariables
cliniques mentionnées plus haut. Le classement des différents
marqueurs en fonction de l’augmentation du risque (RR)
engendrée par chaque élévation de 1 ET de leur taux s’est
établi comme suit : MR-proANP (1,97), NT-proBNP (1,73),
MR-proADM (1,48), CT-proET-1 (1,47) et TnTc (1,37). En
raison de la corrélation relevée entre ces biomarqueurs et
pour tenir compte du fait qu’aucun d’eux n’est encore dosé en
routine dans cette population, nous avons eu recours à un
algorithme de sélection par éliminations successives dénué de
biais pour construire un modèle d’évaluation des différents
marqueurs. Les deux seuls qui se sont révélés aptes à être
inclus dans un modèle où figuraient déjà les covariables
cliniques et qui n’en ont pas été secondairement écartés ont
été le MR-proANP (RR ajusté : 1,79 ; intervalle de confiance
[IC] à 95 % : 1,41 à 2,26 ; p <0,001) et le MR-proADM
(RR ajusté : 1,27 ; IC à 95 % : 1,07 à 1,51 ; p = 0,007).
L’incorporation du MR-proANP, du MR-proADM et du
CT-proET-1 au modèle clinique séparément les uns des autres
Liens relevés entre les taux de biomarqueurs et les événements cliniques dans le groupe placebo
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Biomarqueurs du stress cardiovasculaire dans la maladie coronaire stable
319
Figure 1. Incidences cumulées de l’événement cible composite regroupant le décès de cause cardiovasculaire et l’insuffisance cardiaque
chez les patients du groupe placebo (n = 1 868) de l’essai Prevention of Events With Angiotensin Converting Enzyme (PEACE), en fonction
des quartiles des taux de fragments médians du propeptide natriurétique atrial (MR-proANP) et de la pro-adrénomédulline (MR-proADM),
de fragment C-terminal de la pro-endothéline de type 1 (CT-proET-1) et de copeptine. Les valeurs de p sont celles fournies par le test des
rangs logarithmiques effectué pour examiner la tendance inter-quartiles.
Tableau 3. Liens multivariés relevés entre les taux de biomarqueurs et l’incidence des événements cliniques dans groupe placebo
après ajustement pour les facteurs cliniques
a significativement amélioré le pouvoir de discrimination
(Tableau 4). En revanche, l’ajout de la copeptine ne s’est
traduit par aucune amélioration du critère en question.
L’inclusion conjointe des trois marqueurs biologiques dans
le modèle clinique a fait passer la statistique C de 0,768 à
0,809 et a amélioré la discrimination intégrée de 4,6 % et la
reclassification nette de 0,435 (p ≤0,0005 pour toutes les
10:00:26:07:12
Page 319
analyses). L’ajout du MR-proANP, du MR-proADM et du
CT-proET-1 a été à l’origine d’améliorations uniformes et
significatives de la statistique C dans les modèles multivariés
qui prenaient déjà en compte les covariables cliniques et ce,
que le NT-proBNP, la TnTc, ou les deux associés aient été
ou non présents, eux aussi, dans le modèle ; en revanche,
l’incorporation du NT-proBNP et de la TnTc à un modèle
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Septembre 2012
Tableau 4. Influence des taux de biomarqueurs et des
critères de discrimination et de reclassification dans le
groupe placebo
étaient augmentés (n = 472) ou que les trois étaient augmentés
(n = 317) (Figure 2B). En dissociant les résultats, nous avons
observé que, chez les 2 928 patients dont au plus un seul
biomarqueur était augmenté (soit 79 % de la cohorte
dans laquelle les biomarqueurs avaient été mesurés),
l’administration de trandolapril n’avait pas eu d’impact
bénéfique sur le risque de décès de cause cardiovasculaire ou
d’insuffisance cardiaque (RR : 1,09 ; IC à 95 % : 0,74 à 1,59),
alors que, chez les 789 sujets qui présentaient des élévations
d’au moins deux biomarqueurs (21 % de la cohorte), elle
a significativement diminué l’incidence de l’événement
composite (RR : 0,53 ; IC à 95 % : 0,36 à 0,80 ; p = 0,002,
pinteraction = 0,012 ; Figure 3). Dans ce dernier sous-groupe,
la diminution du risque absolu sur 6 ans a atteint 7,5 %, ce
qui signifie qu’il convient de traiter 14 patients du sous-groupe
en question pendant 6 ans pour prévenir un décès de cause
cardiovasculaire ou une hospitalisation pour insuffisance
cardiaque.
Discussion
qui, outre les covariables cliniques, incluait le MR-proANP, le
MR-proADM et le CT-proET-1 n’a pas entraîné d’amélioration de la statistique C (Tableau XI du supplément de données
uniquement disponible en ligne).
Interaction avec le traitement par le trandolapril
Dans la cohorte totale, tous biomarqueurs confondus,
l’administration de trandolapril a été associée à un RR de
décès de cause cardiovasculaire ou d’insuffisance cardiaque
chiffré à 0,80 (IC à 95 % : 0,61 à 1,05). Il importe toutefois
de noter que, chez les patients dont le taux de MR-proANP,
de MR-proADM ou de CT-proET-1 se situait dans le quartile
le plus élevé et qui, de ce fait, étaient exposés au risque
maximal de décès de cause cardiovasculaire ou d’insuffisance
cardiaque sur la base de ces marqueurs biologiques, le
trandolapril a entraîné une diminution significative de ce
risque, comprise entre 34 et 44 %, alors qu’il n’a eu aucun
effet bénéfique chez les patients qui encouraient des risques
plus faibles (Figure 2A). En revanche, la prescription de
trandolapril n’a entraîné aucune amélioration significative
chez les patients dont le taux de NT-proBNP ou de TnTc se
situait dans le quartile les plus élevé (Figure I du supplément
de données uniquement disponible en ligne).
Nous avons constaté un gradient de bénéfice exercé par le
trandolapril (pinteraction = 0,016) chez les patients selon qu’ils ne
présentaient aucune élévation des nouveaux biomarqueurs
dont les analyses ajustées avaient montré qu’ils étaient
corrélés avec le risque de décès de cause cardiovasculaire ou
d’insuffisance cardiaque (n = 2 037), qu’un seul de ces
marqueurs était augmenté (n = 891), que deux marqueurs
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Dans une analyse exploratoire effectuée sur une vaste cohorte
de patients coronariens stables dont la FEVG était conservée,
nous avons démontré que les élévations des taux de
trois marqueurs biologiques du stress cardiovasculaire
nouvellement décrits constituent des facteurs indépendants
d’augmentation du risque de décès de cause cardiovasculaire
ou d’insuffisance cardiaque. De fait, un lien a pu être établi
entre les taux de MR-proANP, MR-proADM et CT-proET-1
et le décès d’origine cardiovasculaire ou l’insuffisance
cardiaque indépendamment des facteurs cliniques, de la
fonction rénale et de la FEVG ; chaque élévation de 1 ET du
logarithme naturel du taux de ces marqueurs s’est, en effet,
traduite par une augmentation du risque variant de 47 % à
près du double et, chez les patients dont les taux se situaient
dans le quartile le plus élevé, le risque a augmenté à un
niveau compris entre près du triple et plus du quintuple
comparativement à celui observé chez les individus classés
dans le quartile le plus faible. En revanche, un quatrième
biomarqueur, la copeptine, n’a présenté aucun lien propre
avec le risque d’événement cardiovasculaire. Surtout, et
contrairement à ce qui avait été précédemment rapporté
pour d’autres marqueurs, dont le NT-proBNP et la TnTc,6,26,31
l’existence d’une élévation d’un ou plusieurs des trois
biomarqueurs mentionnés a constitué un élément de
caractérisation des patients chez lesquels l’administration
d’un IEC a significativement réduit le risque de décès de cause
cardiovasculaire ou d’insuffisance cardiaque, alors même que,
sur la base des critères cliniques, ils paraissaient n’encourir
qu’un faible risque.
Nous n’avons pas directement mesuré les taux d’ANP,
d’ADM et d’ET-1, mais ceux de leurs prohormones, car
celles-ci sont libérées en proportion équimolaire par rapport
aux hormones vasoactives mais ont une demi-vie plus longue.
Par ailleurs, lorsque cela était possible, nous avons préféré
doser le taux de fragment médian, car ce dernier est plus stable
in vivo et ex vivo que les portions amino- et carboxyterminales de la prohormone, ce qui minimise le risque de
sous-estimation des taux lié à la dégradation précoce des
épitopes majeurs situés aux deux extrémités de la molécule.32
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321
Figure 2. Effets bénéfiques exercés par le trandolapril sur le risque de survenue de l’événement cible composite regroupant le décès de
cause cardiovasculaire (CV) et l’insuffisance cardiaque chez les 3 717 patients de l’essai Prevention of Events With Angiotensin Converting
(PEACE) en fonction de leurs taux de biomarqueurs du stress cardiovasculaire. En A, une distinction a été opérée entre les patients selon que
leurs taux de biomarqueurs du stress cardiovasculaire se situaient dans le quartile le plus élevé (quartile 4) ou dans les quartiles inférieurs
(quartiles 1 à 3). Les valeurs p afférentes à l’interaction ont été de 0,16 pour le taux de fragment médian du propeptide natriurétique atrial
(MR-proANP), de 0,02 pour le taux de fragment médian de la pro-adrénomédulline (MR-proADM), de 0,09 pour le taux de fragment Cterminal de la pro-endothéline de type 1 (CT-proET-1) et de 0,72 pour le taux de copeptine. En B, les patients ont été classés en fonction du
nombre de biomarqueurs (MR-proANP, MR-proADM et CT-proET-1) qui se situaient dans le quartile le plus élevé ; la valeur p afférente à
l’interaction a été de 0,016. En A et B, les losanges figurent l’effet exercé dans la cohorte totale, tous biomarqueurs confondus, le centre
des losanges représentant le risque relatif estimé et les extrémités gauche et droite l’intervalle de confiance (IC) à 95 %. Les carrés et les
cercles figurent les risques relatifs estimés et les traits horizontaux les IC à 95 % afférents à l’effet exercé dans chaque sous-groupe.
RR : risque relatif.
Figure 3. Incidences
cumulées de l’événement cible
composite regroupant le décès
de cause cardiovasculaire
(CV) et l’insuffisance
cardiaque chez les 3 717
patients de l’essai Prevention
of Events With Angiotensin
Converting Enzyme (PEACE)
selon qu’il ne présentaient pas
plus d’un biomarqueur dont le
taux était augmenté (courbes
continues ; la courbe en rouge
correspond aux 1 487 patients
du groupe placebo et la courbe
en bleu aux 1 441 patients
traités par le trandolapril)
ou que les élévations
concernaient deux marqueurs
ou plus (courbes en pointillés ;
la courbe en rouge correspond
aux 381 patients du groupe
placebo et la courbe en bleu
aux 408 patients traités par le
trandolapril). RR : risque relatif ;
IC : intervalle de confiance.
Dans des études menées chez des patients atteints d’insuffisance cardiaque documentée, l’élévation des taux de
MR-proANP, MR-proADM et CT-proET-1 s’est montrée
corrélée avec la mortalité indépendamment des paramètres
cliniques, ces biomarqueurs biologiques ayant, de plus,
fait preuve d’une valeur pronostique et d’un pouvoir
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discriminatoire qui soutiennent avantageusement la
comparaison avec ceux du BNP et/ou du NT-proBNP.13–15
En accord avec ces observations, à l’analyse de notre série
de données, nous avons constaté que, dans le modèle ajusté en
fonction des facteurs cliniques que nous avions construit
pour évaluer les différents biomarqueurs, le MR-proANP et
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le MR-proADM avaient été ceux pour lesquels les
corrélations avaient été les plus puissantes, celles-ci s’étant
révélées supérieures à celles observées pour le NT-proBNP
et pour la TnTc mesurée par une méthode hautement
sensible. Dans la mesure où notre étude avait un fondement
clinique plutôt que mécaniste, nous ne pouvons que spéculer
sur les raisons de cette supériorité, qui peut notamment tenir
à de discrètes différences dans les voies physiopathologiques
qui sous-tendent l’élévation des taux de chacun de ces
biomarqueurs ou aux propriétés analytiques plus favorables
et qui, donc, permettent mieux de dépister les troubles
cardiovasculaires infracliniques. Cela étant, nos données
corroborent et prolongent par plusieurs aspects les
observations rapportées par Schnabel et al7 sur ces marqueurs
biologiques et leurs relations avec l’athérosclérose ; elles
portent, en effet, sur des patients qui n’étaient pas insuffisants
cardiaques à leur entrée dans l’étude et dont les FEVG étaient
connues et ont été incluses dans tous les modèles multivariés ;
notre cohorte de patients avait, en outre, pour origine un
nombre beaucoup plus élevé de centres cliniques et nous
avons spécifiquement axé nos analyses sur les événements
cliniques que les biomarqueurs du stress cardiovasculaire
sont le mieux à même de prédire, à savoir le décès de cause
cardiovasculaire et l’insuffisance cardiaque, plutôt que sur un
événement composite incluant le décès ou l’IDM.
Elément fondamental, alors que les précédentes analyses de
marqueurs biologiques avaient été incluses dans des études de
cohortes observationnelles, nous avons eu la faculté d’étudier
les présents marqueurs dans le cadre d’un essai clinique
randomisé, ce qui nous a permis d’examiner l’interaction
entre leurs taux initiaux et l’efficacité du traitement assigné
par la randomisation en nous exonérant du biais inhérent
à l’évaluation de traitements alloués de façon non randomisée.
En nous appuyant sur plusieurs de ces nouveaux biomarqueurs du stress cardiovasculaire, nous avons pu établir
que, chez près du cinquième des patients coronariens stables
de l’essai, l’administration d’un IEC avait pratiquement réduit
de moitié le risque de décès de cause cardiovasculaire
ou d’insuffisance cardiaque. Nos résultats rejoignent
conceptuellement les observations de Richards et al,33,34
qui avaient montré que la présence de taux augmentés de
biomarqueurs du stress cardiovasculaire permet d’identifier
les patients présentant une dysfonction ventriculaire
gauche d’origine ischémique chez lesquels l’administration
d’un bêtabloquant est bénéfique.
Selon les actuelles recommandations en matière de prise en
charge des patients coronariens stables, la prescription d’un
IEC est conseillée chez ceux dont la FEVG est inférieure à
40 % ; de plus, en partie en raison des données de l’essai
HOPE (Heart Outcomes Prevention Evaluation [étude sur
la prévention des événements cardiaques]), les IEC sont
également recommandés chez les patients exposés à un risque
relativement élevé et/ou qui relèvent d’une autre indication
clinique majeure (telle que la présence d’une hypertension
artérielle, d’un diabète ou d’une néphropathie chronique).35
En revanche, chez les patients qui encourent un risque moins
important, comme cela était le cas de ceux de l’essai PEACE,
dans lequel le taux d’événements enregistré dans le groupe
placebo a été inférieur à celui observé dans le groupe de l’essai
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HOPE qui avait reçu l’IEC, les recommandations stipulent
qu’il est licite, sans que cela soit expressément requis, de
prescrire un IEC dès lors que les facteurs de risque cardiovasculaire sont bien contrôlés et qu’une revascularisation a été
pratiquée. Nos présentes données confortent l’hypothèse
selon laquelle, dans cette population extrêmement vaste de
patients qui, cliniquement, paraissent encourir un risque
moindre, le dosage des taux de biomarqueurs du stress
cardiovasculaire pourrait être un utile auxiliaire pour décider
de l’attitude à adopter. Bien que d’autres études prospectives
doivent être entreprises si la mesure de ces marqueurs
biologiques venait à entrer dans la pratique clinique courante
aux Etats-Unis, l’attitude consistant à asseoir le choix du
traitement médicamenteux à long terme sur une série
de biomarqueurs serait sans doute intéressante en termes de
rapport coût/efficacité.
Notre étude présente plusieurs limites potentielles qu’il
convient d’examiner. La cohorte de l’essai clinique PEACE,
qui était principalement constituée d’hommes blancs âgés de
plus de 50 ans, n’est nullement représentative de la population
générale. Pour autant, les caractéristiques cliniques des
patients inclus dans notre étude sont celles classiquement
observées chez les individus atteints d’une maladie coronaire
stable ; de plus, beaucoup de ces patients recevaient des
bêtabloquants et des hypolipémiants. Les prélèvements
sanguins ont été uniquement effectués dans un sous-groupe
de participants à l’essai principal PEACE ; toutefois, il
n’existait pas de différence cliniquement significative entre les
patients inclus dans notre sous-étude sur les marqueurs
biologiques et ceux qui n’y ont pas pris part. Bien que nous
ayons utilisé des échantillons biologiques stockés, l’éventuelle
dégradation de certains de ces échantillons ne pouvait
qu’avoir un caractère aléatoire quant à son influence sur les
événements cardiovasculaires, de sorte que les erreurs de
classement qui en auraient découlé auraient uniquement
biaisé les résultats dans le sens de l’hypothèse nulle.
L’élaboration du score fondé sur les différents marqueurs
pour évaluer l’interaction avec le traitement doit être
considérée comme exploratoire, car la combinaison optimale
de biomarqueurs et les valeurs seuils de ces derniers
demandent à être validées dans d’autres populations.
L’insuffisance cardiaque ne constituait pas un élément du
critère de jugement principal prédéfini dans le plan
d’organisation de l’essai originel ; elle représente néanmoins
un type d’événement dont il a été clairement établi, dans
d’autres populations, que sa survenue peut être anticipée
par la mesure des taux de biomarqueurs du stress
cardiovasculaire et prévenue par l’administration d’un
IEC.6,19,20,26
Conclusion
Chez les patients apparemment exposés à un faible risque qui
présentent une maladie coronaire stable avec conservation de
la FEVG, la mise en évidence de taux augmentés des nouveaux biomarqueurs du stress cardiovasculaire peut permettre
de dépister ceux d’entre eux qui encourent un risque plus élevé
de décès de cause cardiovasculaire ou d’insuffisance cardiaque
et, par ailleurs, d’identifier ceux chez lesquels la prescription
d’un IEC serait hautement bénéfique.
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Sources de financement
L’essai PEACE a été financé par le National Heart, Lung, and Blood
Institute des Etats-Unis (NHLBI ; contrat N01 HC65149) ainsi que
par Knoll Pharmaceuticals et Abbott Laboratories, qui ont également
fourni le médicament de l’étude. Le travail du Dr Sabatine a été en
partie financé par une bourse R01 HL094390 du NHLBI. Les réactifs
utilisés pour les dosages du MR-proANP, du MR-proADM, du
CT-proET-1 et de la copeptine ont été fournis par B.R.A.H.M.S.
Gmbh (Henningsdorf, Allemagne). Le NHLBI, Knoll Pharmaceuticals, Abbott Laboratories et B.R.A.H.M.S. GmbH se sont
abstenus de toute intervention dans la conception et la conduite
de l’étude ; ils n’ont pas davantage joué de rôle dans le recueil,
le traitement, l’analyse et l’interprétation des données ni dans la
préparation, la révision et l’approbation du présent manuscrit.
Déclarations
5.
6.
7.
Les Drs Sabatine, Morrow et Braunwald ainsi que S. Sloan sont
membres du groupe d’étude TIMI, auquel des bourses de recherche
ont été octroyées par Accumetrics, Amgen, AstraZeneca, Beckman
Coulter, BG Medicine, B.R.A.H.M.S. GmbH, Bristol-Myers Squibb,
CV Therapeutics, Daiichi Sankyo Co Ltd, diaDexus, Eli Lilly & Co,
Genentech, GlaxoSmith-Kline, Integrated Therapeutics, Johnson &
Johnson, Merck & Co, Nanosphere, Novartis Pharmaceuticals,
Nuvelo, Ortho-Clinical Diagnostics, Pfizer, Roche Diagnostics,
Sanofi-Aventis, Siemens et Singulex. Le Dr Sabatine a été rémunéré
pour des conférences de FMC par Bristol-Myers Squibb et diaDexus
et a perçu des honoraires en qualité de consultant d’AstraZeneca,
Bristol-Myers Squibb/Sanofi-Aventis Joint Venture, Daiichi-Sankyo/
Lilly Partnership, Sanofi-Aventis et Singulex. Le Dr Morrow a été
rémunéré pour des conférences de FMC par Eli Lilly, en qualité
de consultant par Beckman-Coulter, Boehringer Ingelheim, Cardiokinetix, Critical Diagnostics, Gilead, Instrumentation Laboratory,
Ikaria, Menarini, Merck, OrthoClinical Diagnostics, Servier,
Roche Diagnostics et Siemens et en tant que membre d’un comité
d’adjudication des événements cliniques par AstraZeneca. Le Dr de
Lemos a bénéficié de dotations émanant de Roche et d’Alere Inc.
(anciennement Biosite) et a été rémunéré en qualité de consultant par
Alere, Johnson & Johnson Roche Diagnostics et Tethys Biomedical.
Le Dr Omland a été rémunéré en qualité de conférencier par Roche
Diagnostics et Abbott Laboratories. Le Dr Jarolim a bénéficié de
bourses de recherche octroyées par Amgen, Beckman-Coulter, Ortho
Clinical Diagnostics, Roche Diagnostics et Siemens Healthcare
Diagnostics ; il a été rémunéré pour des conférences de FMC par
Ortho Clinical Diagnostics et en qualité de consultant par T2 Biosystems. Le Dr Pfeffer a bénéficié de dotations émanant d’Amgen,
Novartis et Sanofi-Aventis et a été rémunéré en qualité de consultant
par Amgen, Anthera, Boehringer Ingelheim, Boston Scientific,
Bristol-Myers Squibb, Cerenis, Eleven Biotherapeutics, GlaxoSmithKline, Hamilton Health Sciences, Karo Bio, Novartis, Roche,
Salutria, Sanofi Aventis, Servier et l’Université d’Oxford. Le Dr
Pfeffer est également co-détenteur avec le Brigham and Women’s
Hospital d’un brevet portant sur l’utilisation des inhibiteurs
du système rénine-angiotensine chez des patients sélectionnés ayant
survécu à un IDM. Les parts qu’il possède dans des accords de licence
avec Novartis et Boehringer (et dont les revenus sont systématiquement reversés à des organismes caritatifs) sont sans lien avec l’activité
commerciale. Le Dr Braunwald a été rémunéré pour sa participation
à des colloques et/ou en tant que consultant par Amorcyte, CardioRentis, CVRx, Daiichi Sankyo, Eli Lilly, Genzyme, Medicines Co
et Merck & Co. Les autres auteurs n’ont aucun conflit d’intérêts
à signaler.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
Références
1. Braunwald E. Biomarkers in heart failure. N Engl J Med. 2008;358:
2148–2159.
2. Wang TJ, Larson MG, Levy D, Benjamin EJ, Leip EP, Omland T,
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PERSPECTIVE CLINIQUE
Les avis demeurent partagés quant à l’impact bénéfique des inhibiteurs de l’enzyme de conversion de l’angiotensine chez les patients à faible risque qui
présentent une maladie coronaire stable mais sont indemnes d’insuffisance cardiaque ; cela étant, les actuelles recommandations stipulent qu’il est licite, sans
que cela soit expressément requis, de prescrire un tel médicament dès lors que les facteurs de risque cardiovasculaire sont bien contrôlés et qu’une
revascularisation a été pratiquée. Dans la présente étude, nous démontrons que l’élévation des taux de trois nouveaux biomarqueurs du stress cardiovasculaire, à savoir les fragments médians du propeptide natriurétique atrial et de la pro-adrénomédulline et le fragment C-terminal de la pro-endothéline de
type 1, contribue à augmenter le risque de décès de cause cardiovasculaire et d’insuffisance cardiaque indépendamment des facteurs cliniques (les risques
relatifs ajustés par élévation de 1 ET du taux mesuré ayant été respectivement estimés à 1,97, 1,48 et 1,47 ; p ≤0,002 pour chaque marqueur biologique). De
plus, l’existence d’une élévation d’un ou plusieurs des trois biomarqueurs mentionnés est apparue comme un élément de caractérisation des patients chez
lesquels l’administration d’un inhibiteur de l’enzyme de conversion de l’angiotensine a significativement réduit le risque de décès de cause cardiovasculaire
ou d’insuffisance cardiaque. Plus précisément, l’administration de trandolapril a significativement abaissé le risque en question chez les patients dont les taux
d’au moins deux marqueurs étaient augmentés (risque relatif : 0,53 ; intervalle de confiance à 95 % : 0,36 à 0,80), alors qu’il n’a eu aucune influence
bénéfique en l’absence d’élévation de ces biomarqueurs ou lorsque le taux d’un seul d’entre eux était augmenté (risque relatif : 1,09 ; intervalle de confiance à
95 % : 0,74 à 1,59 ; pinteraction = 0,012). Il apparaît donc que, chez les patients coronariens stables dont la FEVG est conservée, la mise en évidence de taux
augmentés des nouveaux biomarqueurs du stress cardiovasculaire permet de dépister ceux d’entre eux qui encourent un risque plus élevé de décès de cause
cardiovasculaire ou d’insuffisance cardiaque et, par ailleurs, d’identifier ceux chez lesquels la prescription d’un inhibiteur de l’enzyme de conversion
de l’angiotensine serait hautement bénéfique.
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