Download Impact of Serial Troponin Release on Outcomes in Patients With

Impact of Serial Troponin Release on Outcomes in Patients
With Acute Heart Failure
Analysis From the PROTECT Pilot Study
Christopher M. O’Connor, MD; Mona Fiuzat, PharmD; Carlo Lombardi, MD; Kenji Fujita, MD;
Gang Jia, PhD; Beth A. Davison, PhD; John Cleland, MD; Daniel Bloomfield, MD;
Howard C. Dittrich, MD; Paul DeLucca, MD; Michael M. Givertz, MD; George Mansoor, MD;
Piotr Ponikowski, MD; John R. Teerlink, MD; Adriaan A. Voors, MD; Barry M. Massie, MD;
Gad Cotter, MD; Marco Metra, MD
Downloaded from http://circheartfailure.ahajournals.org/ by guest on May 2, 2017
Background—Cardiac troponin T (cTnT) elevation is common and is a predictor of outcomes in patients with acute heart
failure (AHF). The degree and progression of cTnT release during hospitalization of patients with AHF is unclear. We
evaluated the incidence of cTnT release during AHF hospitalization and the relationship of cTnT release with outcomes.
Methods and Results—The Placebo-controlled Randomized study of the selective A(1) adenosine receptor antagonist
rolofylline for patients hospitalized with acute heart failure and volume Overload to assess Treatment Effect on
Congestion and renal funcTion (PROTECT) pilot study was a multicenter, double-blind study of patients with AHF.
Measurements of cTnT were collected at randomization and days 2, 3, 4, and 7. Patients were classified on the basis
of their serum cTnT levels at baseline: positive (⬎0.03 ng/mL), detectable (⬎0.01 ng/mL), and negative (ⱕ0.01 ng/mL).
A detectable cTnT level developed during the study (after baseline) was classified as cTnT conversion: 288 patients
were included; 172 (60%) patients had detectable cTnT levels and 97 (34%) had positive values (⬎0.03 ng/mL) at
baseline. Of the 116 patients with negative troponin at baseline, 24 (21%) had elevated cTnT levels by day 7. On
multivariable analysis, positive cTnT at baseline was an independent predictor of the composite end point of
cardiovascular/renal rehospitalization or death at 60 days (hazard ratio, 1.84; 95% confidence interval, 1.04 –3.26;
P⫽0.036). Kaplan-Meier curves showed similar worse outcomes in patients with troponin conversion and positive
troponin at baseline.
Conclusions—There was a high prevalence of baseline cTnT elevation in this cohort; 21% of those negative at baseline
converted to detectable levels by day 7. Positive troponin at baseline, and conversion to positive levels, were associated
with worse outcomes at 60 days.
Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00328692 and NCT00354458.
(Circ Heart Fail. 2011;4:724-732.)
Key Words: cardiac troponin 䡲 acute heart failure 䡲 rolofylline
A
have been shown to be elevated in some ambulatory chronic
heart failure (HF) patients and in patients with AHF and may
be markers of poor prognosis.7–12
cute heart failure (AHF) is the most common cause of
hospitalization in patients ⬎65 years of age.1 Despite
advances in medical treatment, morbidity and mortality
remain high.2 The pathophysiologic mechanisms of acute
decompensation and the persistently high short-term mortality may be related to abnormal hemodynamics, neurohormonal and inflammatory activation, volume overload of
various etiologies, renal damage, and myocardial injury.3– 6
Biological markers related to these mechanisms are therefore
potentially useful in patients with AHF. Troponins I and T
Clinical Perspective on p 732
The mechanism of troponin release in patients with HF is
multifactorial. Abnormal hemodynamics with high left ventricular end-diastolic pressure and low aortic and coronary
perfusion pressure, adrenergic stimulation, increased inflammatory cytokines, and excessive tachycardia due to arrhyth-
Received December 23, 2010; accepted August 2, 2011.
From the Duke Clinical Research Institute, Duke University Medical Center, Durham, NC (C.M.O., M.F.); the Department of Experimental and
Applied Medicine, University of Brescia, Brescia, Italy (C.L., M.M.); Merck Research Laboratories, Rahway, NJ (K.F., G.J., D.B., H.D., P.D., G.M.);
Momentum Research (B.D., G.C.), Durham, NC; University of Hull, United Kingdom (J.C.); Brigham and Women’s Hospital, Harvard Medical School,
Boston, MA (M.G.); Medical University, Clinical Military Hospital, Wroclaw, Poland (P.P.); University of California, San Francisco, and San Francisco
VAMC, San Francisco, CA (B.M., J.T.); and University Medical Center Groningen, Gronigen, The Netherlands (A.V.).
Guest Editor for this article was Gregg C. Fonarow, MD.
Correspondence to Christopher M. O’Connor, MD, DUMC Box 3356, Durham, NC 27705. E-mail [email protected]
© 2011 American Heart Association, Inc.
Circ Heart Fail is available at http://circheartfailure.ahajournals.org
724
DOI: 10.1161/CIRCHEARTFAILURE.111.961581
O’Connor et al
Downloaded from http://circheartfailure.ahajournals.org/ by guest on May 2, 2017
mias such as rapid atrial fibrillation may all favor myocardial
ischemia, loss of cell membrane integrity, and myocardial
cell death with the mechanisms of necrosis and apoptosis.13–15
Concomitant therapy with inotropic and vasodilating agents,
especially when administered in combination or by use of
agents that have both pharmacological effects, such as milrinone or levosimendan, may exacerbate all of these factors and
lead to increased mortality.16
Recent data suggest that elevated troponin concentrations
are a predictor of poor outcomes in patients with AHF.7
However, this study only assessed the role of troponin
concentrations at the time of admission with respect to the
prediction of in-hospital mortality. Serial measurements of
troponin plasma levels during hospitalization were assessed
in 2 studies to date, which demonstrated that troponin release
commonly occurs and is associated with poor outcome in
these clinical settings. In both studies, approximately 8 –10%
of patients who were negative at baseline had an elevated
troponin during hospitalization.17,18
The recently conducted PROTECT pilot study tested the
effects of the selective adenosine A1 receptor antagonist
rolofylline in patients with AHF and renal insufficiency.19 In
the present analysis, we evaluated the magnitude and time
sequence of troponin release during initial hospitalization of
patients with AHF and the relationship of this troponin
release with subsequent short-term outcomes.
Methods
Trial Design and Patient Population
The PROTECT pilot study was a multicenter, double-blinded study,
randomly assigning patients with AHF and renal insufficiency,
defined as a creatinine clearance between 20 to 80 mL/min using the
Cockcroft-Gault formula,20 to intravenous rolofylline or placebo
within 24 hours of admission. The details of the design, results, and
conclusions of this trial have been previously published.19 Eligible
patients were ⱖ18 years of age and admitted with a primary
diagnosis of AHF. A diagnosis of AHF required the following before
random assignment: dyspnea at rest or minimal exertion, clinical
evidence of fluid overload, and elevated natriuretic peptide levels
(brain natriuretic peptide [BNP] ⬎250 pg/mL or NT proBNP ⬎1000
pg/mL). Exclusion criteria included systolic blood pressure ⬍95 or
⬎160 mm Hg; treatment with an inotropic agent, vasopressor, or
vasodilator (except intravenous nitrates); mechanical support; acute
contrast-induced nephropathy; resistant hypokalemia; severe pulmonary disease; previous cardiac transplantation; and evidence of acute
coronary syndrome within 2 weeks of admission.
Serum Troponin T Measurements
Blood sample measurements of cardiac troponin T (cTnT) were
collected at time of enrollment (day 1) and on days 2, 3, 4, and 7.
Serum was stored at ⫺7°C and shipped to the central core laboratory
for analysis. Troponin levels were measured with a commercially
available high sensitivity assay (Elecsys Troponin T STAT assay,
Roche Diagnostics, Indianapolis, IN).
Patients were classified based on their serum cardiac troponin T
levels at baseline: positive (⬎0.03 ng/mL), detectable (⬎0.01 ng/
mL), and negative (ⱕ0.01 ng/mL). Cardiac troponin conversion was
defined as going from undetectable cTnT at baseline to having any
detectable level during the hospitalization.
Plasma cTnT levels were measured after completion of the
study, and patients’ treatments or follow-ups were not influenced
by their knowledge. Patient demographics, baseline characteristics, medical history, and medications were collected at time of
random assignment.
Troponin Release and Outcomes in AHF Patients
725
End Points
The primary end point of the PROTECT trial was a composite
trichotomous end point, designed to capture improvement of dyspnea
and adverse events that occurred after admission, including worsening HF despite treatment or worsening renal function. Patient were
classified as success, failure, or unchanged. Treatment success was
defined as an improvement in dyspnea (reported by the patient, using
a 7-point Likert scale, as moderately or markedly better compared
with study start) determined at 24 and 48 hours after the start of study
drug and not meeting criteria for treatment failure. Treatment failure
was defined as death; worsening HF, defined as physiciandetermined assessment (based on history, physical examination, and
chart review) of worsening symptoms or signs of HF occurring ⬎24
hours after the start of study drug to day 7 or discharge, whichever
occurred first; early HF readmission (occurring within 7 days of
study drug initiation); or persistent renal impairment defined as an
increase in serum creatinine of ⱖ0.3 mg/dL at day 7 and day 14.
Patients were classified as unchanged if neither criteria for success or
failure were met.
In this post hoc analysis, the PROTECT primary end point was
calculated on the basis of baseline cTnT level, using logistic
regression with a 3-level outcome and the proportional odds assumption. We also evaluated the association of baseline cTnT level or
conversion to detectable troponin T during hospitalization with the
short-term end point of in-hospital worsening HF or death by day 7,
based on troponin at baseline and conversion to any detectable level.
Finally, we evaluated a composite of cardiovascular (CV)/renal
rehospitalization or death by 60 days, based on troponin at baseline
and conversion to any detectable level.
Statistical Analysis
Continuous variables with normal distribution were expressed as
mean⫾SD and medians (25th, 75th percentile) for other continuous
variables. Comparisons of demographic and clinical baseline characteristics, medical history, and medications were evaluated by the
Student t test for continuous variables and the ␹2 test for categorical
variables. Multivariate analysis for the primary end point was
performed using multiple logistic regression with positive and
detectable troponin T variables analyzed as dichotomous variables.
The model was adjusted for baseline clinical and laboratory characteristics. For the clinical end points, models were developed using
candidate sets of predictor variables for possible model inclusion.
The candidate variables represented a broad range of characteristics,
which were classified as baseline characteristics, medical history,
and laboratory values. A Cox proportional hazards backward selection algorithm was applied using a nominal 0.25 critical value for
model inclusion. A candidate predictor was included in the model if
it met the 0.25 critical significance value.
All reported probability values are 2-sided, and a probability value
⬍0.05 was considered statistically significant.
The present study was conducted according to the principles stated
in the Declaration of Helsinki. The study protocol was approved by
the ethics committee and institutional review boards for each
participating site, and all patients signed the informed consent form
before participation in the study.
Results
Patient Population
Of 301 patients enrolled in the PROTECT pilot study, 288
had troponin T levels evaluable for inclusion into this study.
There were no clinically important differences in the baseline
characteristics of the excluded patients. The demographics
and baseline characteristics of the population are shown in
Table 1. The mean age of the overall cohort was 70.6 years,
and 59% were male. The clinical profile of the patients was
similar to large acute HF registries.10,21 Most patients received optimal medical treatment, as recommended by international guidelines, before hospitalization.22,23
726
Table 1.
Circ Heart Fail
November 2011
Baseline Characteristics
Baseline Troponin T
Total
(n⫽288)
Age, median (25th, 75th), y
Male
73.00 (65.00, 77.50)
Negative,
ⱕ0.01 ng/mL
(n⫽116)
Detectable,
⬎0.01 ng/mL
(n⫽172*)
Positive,
⬎0.03 ng/mL
(n⫽97)
74.00 (65.00, 78.00)
71.00 (64.00, 77.00)
71.00 (63.00, 77.00)
171 (59.38)
59 (50.86)
112 (65.12)
67 (69.07)
6 (2.20)
3 (2.75)
3 (1.83)
2 (2.22)
2
43 (15.75)
13 (11.93)
30 (18.29)
17 (18.89)
3
114 (41.76)
44 (40.37)
70 (42.68)
35 (38.89)
4
110 (40.29)
49 (44.95)
61 (37.20)
36 (40.00)
History of ischemic heart disease
211 (73.78)
87 (75.00)
124 (72.94)
64 (67.37)
History of MI
157 (54.51)
62 (53.45)
95 (55.23)
44 (45.36)
History of hypertension
237 (82.29)
98 (84.48)
139 (80.81)
75 (77.32)
History of diabetes
150 (52.08)
47 (40.52)
103 (59.88)
60 (61.86)
History of AF/flutter
133 (46.34)
62 (53.91)
71 (41.28)
33 (34.02)
NYHA class
1
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Day 1 creatinine, mean⫾SD, mg/dL
Median (25th, 75th)
1.53⫾0.659
1.30 (1.10, 1.80)
1.23⫾0.406
1.20 (0.90, 1.40)
1.72⫾0.719
1.50 (1.20, 2.10)
1.79⫾0.728
1.70 (1.20, 2.20)
CrCl, mean⫾SD, mL/min
57.16⫾26.362
64.31⫾27.290
52.37⫾24.665
50.91⫾24.839
Median (25th, 75th)
52.43 (38.02, 72.42)
62.11 (46.25, 77.83)
47.84 (35.24, 66.85)
46.27 (32.99, 62.20)
Screening BNP, mean⫾SD, pg/mL
1527.1⫾1469.13
955.17⫾858.422
1746.3⫾1596.42
1842.4⫾1899.17
Screening NT proBNP, mean⫾SD, pg/mL
4009.4⫾5069.87
2693.0⫾1590.06
5104.4⫾6520.18
4904.9⫾6625.14
28.86 (25.52, 33.10)
29.20 (25.51, 32.82)
28.65 (25.55, 33.21)
28.73 (25.47, 32.87)
BMI, median (25th, 75th), kg/m2
History of ICD
History of pacemaker
ACE inhibitor at admission
ARB at admission
␤-Blocker at admission
49 (17.01)
17 (14.66)
32 (18.60)
13 (13.40)
33 (11.46)
16 (13.79)
17 (9.88)
8 (8.25)
165 (57.49)
75 (65.22)
90 (52.33)
50 (51.55)
37 (13.07)
17 (15.04)
20 (11.76)
8 (8.25)
194 (68.07)
82 (71.30)
112 (65.88)
58 (59.79)
29 (29.90)
Aldosterone antagonist at admission
98 (34.63)
41 (35.96)
57 (33.73)
Hydralazine/oral nitrate combination at admission
10 (3.51)
0 (0.00)
10 (5.88)
6 (6.19)
Intravenous nitrates at admission
33 (11.58)
15 (13.04)
18 (10.59)
11 (11.34)
Digoxin at admission
75 (26.60)
31 (27.19)
44 (26.19)
23 (24.21)
Baseline sodium, mean⫾SD, mEq/L
Median (25th, 75th)
Baseline hemoglobin, mean⫾SD, g/dL
Median (25th, 75th)
Baseline BUN, mean⫾SD, mg/dL
Median (25th, 75th)
Systolic blood pressure, median (25th, 75th), mm Hg
Mean⫾SD
Heart rate, median (25th, 75th), bpm
Mean⫾SD
138.98⫾4.31
140.00 (137.00, 142.00)
139.98⫾3.62
140.00 (138.00, 142.00)
138.31⫾4.61
139.00 (136.00, 141.00)
137.92⫾5.11
138.00 (135.00, 142.00)
12.78⫾1.98
13.16⫾1.99
12.53⫾1.94
12.18⫾1.77
12.60 (11.50, 14.30)
13.20 (11.80, 14.50)
12.40 (11.10, 13.90)
12.10 (10.95, 13.20)
32.87⫾17.01
25.59⫾11.78
37.73⫾18.22
41.26⫾19.35
28.00 (20.00, 40.00)
21.50 (17.00, 31.00)
34.00 (24.00, 48.00)
37.00 (26.00, 55.00)
130.00 (110.00, 140.00)
130.00 (111.00, 145.00)
128.00 (110.00, 140.00)
126.00 (110.00, 140.00)
127.04⫾18.87
129.32⫾19.17
125.51⫾18.57
124.19⫾19.05
78.00 (68.00, 90.00)
75.50 (65.50, 90.00)
80.00 (70.00, 90.00)
78.00 (70.00, 90.00)
79.82⫾15.61
78.95⫾17.16
80.41⫾14.49
80.52⫾14.86
ACE indicates angiotensin-converting enzyme; AF, atrial fibrillation; ARB, angiotensin receptor blocker; BMI, body mass index; BNP, brain natriuretic peptide; bpm,
beats per minute; BUN, blood urea nitrogen; CrCl, creatinine clearance; ICD, implantable cardioverter-defibrillator; MI, myocardial infarction; and NYHA, New York Heart
Association.
*Includes group of patients positive (⬎0.03) at baseline.
Values are presented as n (%) unless otherwise indicated.
Prevalence of Troponin Release
One hundred seventy-two (60%) patients had detectable
(⬎0.01 ng/mL) cTnT levels, and 97 (34%) patients had
positive values of cTnT (⬎0.03 ng/mL) at baseline. By day 7,
196 patients (68%) had detectable troponin T, and 92 (32%)
remained negative.
Of the 116 patients with negative troponin T at baseline, 24
(21%) had a detectable cTnT level ⬎0.01 ng/mL by day 7
O’Connor et al
Table 2.
Troponin Release and Outcomes in AHF Patients
727
Clinical Characteristics of Converters
Troponin T
Total
(n⫽288)
Age, median (25th, 75th), y
Male
73.00 (65.00, 77.50)
All Negative
(n⫽92)
Converter*
(n⫽24)
Detectable at Baseline
(n⫽172)
74.00 (65.00, 78.00)
74.00 (65.50, 77.50)
71.00 (64.00, 77.00)
171 (59.38)
43 (46.74)
16 (66.67)
P
Value†
0.63
112 (65.12)
0.08
0.97
NYHA class
1
6 (2.20)
3 (3.49)
0 (0.00)
3 (1.83)
2
43 (15.75)
10 (11.63)
3 (13.04)
30 (18.29)
3
114 (41.76)
34 (39.53)
10 (43.48)
70 (42.68)
4
110 (40.29)
39 (45.35)
10 (43.48)
61 (37.20)
History of ischemic heart disease
211 (73.78)
69 (75.00)
18 (75.00)
124 (72.94)
1.00
History of MI
157 (54.51)
50 (54.35)
12 (50.00)
95 (55.23)
0.70
History of hypertension
237 (82.29)
77 (83.70)
21 (87.50)
139 (80.81)
0.76
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History of diabetes mellitus
150 (52.08)
33 (35.87)
14 (58.33)
103 (59.88)
0.05
History of AF/flutter
133 (46.34)
49 (53.85)
13 (54.17)
71 (41.28)
0.98
Day 1 creatinine value, median (25th, 75th)
CrCl (calculated), median (25th, 75th)
1.30 (1.10, 1.80)
1.15 (0.90, 1.40)
1.20 (0.90, 1.55)
1.50 (1.20, 2.10)
0.29
52.43 (38.02, 72.42)
64.19 (46.40, 78.67)
55.13 (44.66, 77.09)
47.84 (35.24, 66.85)
0.37
Screening BNP, median (25th, 75th), pg/mL
1016.0 (510.00, 2240.0)
490.50 (394.00, 1170.0)
729.00 (489.00, 2551.0)
1393.0 (610.00, 2434.5)
0.25
Screening NT proBNP, median (25th, 75th),
pg/mL
3000.0 (2193.0, 3000.0)
2769.0 (1793.0, 3000.0)
2681.0 (1401.0, 3000.0)
3000.0 (3000.0, 3000.0)
0.21
28.86 (25.52, 33.10)
29.48 (25.41, 33.31)
27.97 (25.86, 29.92)
28.65 (25.55, 33.21)
BMI, median (25th, 75th), kg/m2
History of AICD
History of pacemaker
ACE inhibitor at admission
ARB at admission
0 (0.00)
32 (18.60)
0.25
49 (17.01)
17 (18.48)
0.02
33 (11.46)
12 (13.04)
4 (16.67)
17 (9.88)
0.74
165 (57.49)
62 (68.13)
13 (54.17)
90 (52.33)
0.20
37 (13.07)
12 (13.48)
5 (20.83)
20 (11.76)
0.35
194 (68.07)
66 (72.53)
16 (66.67)
112 (65.88)
0.57
Aldosterone antagonist at admission
98 (34.63)
33 (36.67)
8 (33.33)
57 (33.73)
0.76
Hydralazine/oral nitrate combination at
admission
10 (3.51)
0 (0.00)
0 (0.00)
10 (5.88)
NA
␤-Blocker at admission
Intravenous nitrates at admission
33 (11.58)
13 (14.29)
2 (8.33)
18 (10.59)
0.73
Digoxin at admission
75 (26.60)
24 (26.67)
7 (29.17)
44 (26.19)
0.81
Sodium, median (25th, 75th)
HGB, median (25th, 75th)
BUN, median (25th, 75th)
Systolic BP, median (25th, 75th), mm Hg
Pulse, median (25th, 75th)
140.00 (137.00, 142.00)
140.00 (138.00, 142.00)
140.00 (138.00, 142.50)
139.00 (136.00, 141.00)
0.47
12.60 (11.50, 14.30)
13.20 (11.90, 14.50)
12.55 (10.70, 14.50)
12.40 (11.10, 13.90)
0.16
28.00 (20.00, 40.00)
21.00 (17.00, 30.00)
25.50 (19.50, 35.50)
34.00 (24.00, 48.00)
0.10
130.00 (110.00, 140.00)
130.00 (111.00, 145.00)
129.00 (111.00, 148.00)
128.00 (110.00, 140.00)
0.96
78.00 (68.00, 90.00)
72.00 (65.00, 91.00)
79.00 (70.00, 89.00)
80.00 (70.00, 90.00)
0.59
Randomized treatment
Placebo
74 (25.69)
23 (25.0)
9 (37.50)
42 (24.42)
Rolofylline, 10 mg
70 (24.31)
21 (22.83)
7 (29.17)
42 (24.42)
Rolofylline, 20 mg
74 (25.69)
21 (22.83)
5 (20.83)
48 (27.91)
Rolofylline, 30 mg
70 (24.31)
27 (29.35)
3 (12.50)
40 (23.26)
0.32
ACE indicates angiotensin-converting enzyme; AF, atrial fibrillation; AICD, automatic implantable cardioverter-defibrillator; ARB, angiotensin receptor blocker; BMI,
body mass index; BNP, brain natriuretic peptide; BP, blood pressure; BUN, blood urea nitrogen; CrCl, creatinine clearance; HGB, hemoglobin; MI, myocardial infarction;
and NYHA, New York Heart Association.
*Conversion to any detectable troponin by day 7.
†Comparison between converters and negative troponin at day 7.
Values presented as n (%) unless otherwise indicated.
(cTnT converters). The characteristics of those who were
converters and those who did not convert are shown in Table
2. There were no important differences in clinical characteristics between those who converted to any detectable levels of
troponin T by day 7 compared with those who remained
negative, except that patients with detectable troponin T by day
7 were more often diabetic (P⫽0.046) and more often had an
automatic implantable cardioverter-defibrillator without recent
firing (P⫽0.02). Of note, no patient with detectable cTnT at
baseline dropped to having undetectable levels after baseline.
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Circ Heart Fail
Table 3.
November 2011
Outcomes by Troponin T Release (Cutoff, 0.01 ng/mL): Univariable Analysis
Baseline Troponin T
Total (n⫽288)
ⱕ0.01 ng/mL
(n⫽116)
⬎0.01 ng/mL
(n⫽172)
129 (44.79)
54 (46.55)
75 (43.60)
Unchanged
97 (33.68)
45 (38.79)
52 (30.23)
Failure
62 (21.53)
17 (14.66)
45 (26.16)
76 (26.39)
20 (17.24)
56 (32.56)
0.005/2.01†
24 (8.33)
4 (3.25)
20 (11.63)
0.02/3.49†
59 (20.49)
18 (15.52)
41 (23.84)
0.08/1.64†
26 (9.03)
5 (4.31)
21 (12.21)
0.03/2.94
P Value/OR
or HR
Primary outcome
Success
0.19/0.74*
Day 60 CV/renal rehospitalization or death
Day 60 death
Day 60 CV/renal rehospitalization
In-hospital (up to day 7) worsening HF or death
In-hospital (up to day 7) death
In-hospital (up to day 7) worsening HF
2 (0.69)
0
2 (1.16)
24 (8.36)
5 (4.31)
19 (11.11)
0.95/NA
0.05/2.67†
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CV indicates cardiovascular; HF, heart failure; HR, hazard ratio; and OR, odds ratio.
*OR: This indicates that in patients with troponin ⬍0.01, compared with patients with troponin ⬎0.01, there were
trends toward greater proportions of patients with marked or moderately improved dyspnea and fewer patients with
death, worsening heart failure, or worsening renal function (not statistically significant).
†HR: Values are presented as n (%) unless otherwise indicated.
There was no difference in worsening of creatinine clearance by day 7 in the converter group and no propensity of
converters to have worse renal function. Additionally, we
examined patients with coronary artery disease as a subset of
interest, defined as patients with a history of myocardial
infarction, coronary artery bypass surgery, or percutaneous
coronary intervention. There was no difference in the incidence of troponin T release, conversion, or outcomes in this
subset of patients compared with the overall study cohort.
There was no statistical evidence that rolofylline was
associated with an increased risk of troponin T release
compared with placebo. Although the numbers were small,
the number of converters decreased as the dose of rolofylline
increased, a finding that contradicts evidence suggesting
adenosine A1 receptor stimulation is cardioprotective.24
Table 4.
Outcomes
Composite Trichotomous End Point
In patients with either detectable troponin T or positive
troponin T at baseline, there was no difference in the results
observed for the trichotomous end point (Tables 3 and 4)
compared with patients who were negative at baseline. Those
patients who had positive troponin T levels at baseline or
converted to any detectable level of troponin T were more
often treatment failures and less often had treatment success
(Table 5).
Short-Term End Point
On univariable analysis, any detectable troponin T at baseline
was associated with a nearly 3-fold (hazard ratio [HR], 2.94;
Outcomes by Troponin T release (Cutoff, 0.03 ng/mL): Univariate Analysis
Baseline Troponin T
Total (n⫽288)
ⱕ0.03 ng/mL ⬎0.03 ng/mL
(n⫽191)
(n⫽97)
Primary outcome
Success
Unchanged
Failure
P Value/OR
or HR
0.21/0.75*
129 (44.79)
88 (46.07)
41 (42.27)
97 (33.68)
68 (35.60)
29 (29.90)
62 (21.53)
35 (18.32)
27 (27.84)
76 (26.39)
38 (19.90)
38 (39.18)
⬍0.001/2.19†
Day 60 death
24 (8.33)
8 (4.19)
16 (16.49)
0.001/4.25†
Day 60 CV/renal rehospitalization
59 (20.49)
34 (17.80)
25 (25.77)
0.07/1.61†
26 (9.03)
12 (6.28)
14 (14.43)
0.03/2.40†
2 (0.69)
1 (0.52)
1 (1.03)
0.63/1.98†
24 (8.36)
11 (5.76)
13 (13.54)
0.03/2.45†
Day 60 CV/renal rehospitalization or death
In-hospital (up to day 7) worsening HF or death
In-hospital (up to day 7) death
In-hospital (up to day 7) worsening HF
CV indicates cardiovascular; HF, heart failure; HR, hazard ratio; and OR, odds ratio.
*OR: This indicates that in patients with troponin ⬍0.01, compared with patients with troponin ⬎0.01, there were
trends toward greater proportions of patients with marked or moderately improved dyspnea and fewer patients with
death, worsening heart failure, or worsening renal function (not statistically significant).
†HR.
Values are presented as n (%) unless otherwise indicated.
O’Connor et al
Table 5.
Troponin Release and Outcomes in AHF Patients
729
Outcomes by Troponin T Conversion
Troponin T
Total
(n⫽288)
All Negative
(n⫽92)
Converter*
(n⫽24)
Detectable
at Baseline
(n⫽172)
129 (44.79)
46 (50.00)
8 (33.33)
75 (43.60)
Unchanged
97 (33.68)
36 (39.13)
9 (37.50)
52 (30.23)
Failure
62 (21.53)
10 (10.87)
7 (29.17)
45 (26.16)
Day 60 CV/renal rehospitalization or death
76 (26.39)
12 (13.04)
8 (33.33)
56 (32.56)
0.02
In-hospital (up to day 7) worsening HF or death
26 (9.03)
3 (3.26)
2 (8.33)
21 (12.21)
0.29
P
Value†
Primary outcome
Success
0.04
CV indicates cardiovascular; HF, heart failure.
*Baseline, ⱕ0.01; after baseline, ⬎0.01. †P value for converter versus negative troponin.
Values are presented as n (%) unless otherwise indicated.
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P⫽0.03) increase in the risk of the short-term outcome of
death or in-hospital worsening HF by day 7 (Table 3).
Positive troponin T at baseline conferred a doubling risk of this
end point, which occurred in 14% of patients with positive
troponin T compared with 6% of patients with troponin T ⬍0.03
ng/mL at baseline (HR, 2.4; P⫽0.03; Table 4).
On multivariable analysis, both detectable and positive
troponin T at baseline indicated a greater risk for the
short-term end point compared with those who were negative,
but this difference did not achieve statistical significance
(Table 6).
Those who converted to any detectable level of troponin T
did not appear to have an increased risk of in-hospital
mortality or worsening HF compared with those who were
negative at baseline (P⫽0.29).
CV/Renal Rehospitalization or Death at 60 Days
On univariable analysis, detectable troponin T (⬎0.01 ng/
mL) at baseline conferred a doubling of the risk (HR, 2.01;
P⫽0.005) for the composite end point of CV/renal rehospitalization or death at 60 days, compared with patients with
negative troponin T at baseline. In particular, these patients
had a 3.5-fold increased risk of death at 60 days (P⫽0.023).
Likewise, positive troponin T at baseline was associated with
a doubling of the risk for cardiovascular/renal hospitalization
or death at 60 days (HR, 2.19; P⬍0.001), with a 4-fold
increased risk of death at 60 days (HR, 4.25; P⫽0.001).
On multivariable analysis, positive levels of cardiac troponin T at baseline were confirmed to be an independent
predictor of the composite end point of CV/renal rehospitalization or death at 60 days (HR, 1.84; 95% confidence
interval [CI], 1.04 –3.26; P⫽0.036), whereas detectable troponin T at baseline was not associated with a statistically
significant increase in risk for this end point (HR, 1.23; 95%
CI, 0.64 –2.35; P⫽0.54, Table 7). In the group that converted
to any detectable troponin T, there was a higher incidence of
the composite end point compared with those who remained
negative throughout hospitalization (33% versus 13%,
P⫽0.019), which was similar to those who were detectable at
baseline (33%).
Kaplan-Meier curves showed similar worse outcomes in
patients with troponin T conversion and positive troponin T
levels at baseline, compared with those who were negative
(Figures 1 and 2).
Discussion
To our knowledge, this study represents the largest cohort to
date of AHF patients in which serial troponin T levels were
correlated with outcomes. This analysis confirms that troponin T elevation at baseline is common in patients with AHF
and mild-to-moderate renal dysfunction and is related to poor
Table 6. In-Hospital (Up to Day 7) Worsening HF or Death:
Multivariable Analysis
HR (95% CI)
P Value
Baseline troponin ⬎0.01*
2.63 (0.84, 8.22)
0.10
Baseline troponin ⬎0.03*
1.96 (0.71, 5.45)
0.20
Age of subject
1.02 (0.97, 1.08)
0.45
Male
1.52 (0.50, 4.62)
0.46
Baseline weight
1.02 (0.99, 1.06)
0.15
History of hypertension
3.16 (0.64, 15.67)
0.16
History of diabetes
0.85 (0.31, 2.38)
0.76
History of asthma, bronchitis, or COPD
2.48 (1.04, 5.94)
0.04
History of AF/flutter
0.59 (0.23, 1.53)
0.28
History of stroke, beyond 2 y
0.52 (0.07, 4.13)
0.53
History of ischemic heart disease
1.37 (0.47, 4.01)
0.56
Systolic blood pressure
0.98 (0.95, 1.01)
0.16
Heart rate
1.02 (0.98, 1.05)
0.35
Screening BNP ⬎500 or NT proBNP ⬎2000
1.10 (0.35, 3.43)
0.87
BUN
1.03 (1.00, 1.06)
0.10
Hemoglobin
0.97 (0.76, 1.28)
0.91
Sodium
1.09 (0.97, 1.24)
0.15
Day 1 creatinine value
0.24 (0.06, 0.95)
0.04
Randomized treatment†
1.00 (0.65, 1.54)
0.99
AF indicates atrial fibrillation; BNP, brain natriuretic peptide; BUN, blood urea
nitrogen; CI, confidence interval; COPD, chronic obstructive pulmonary disease;
HR, hazard ratio.
*Relative to negative troponin group. Models were run separately with
“baseline troponin ⬎0.01” and “baseline troponin ⬎0.03.” Because results for
other variables were very similar in the 2 models, only those for the model with
“baseline troponin ⬎0.01” are presented.
†Linear dose trend in the order of placebo, 10 mg, 20 mg, and 40 mg.
730
Circ Heart Fail
November 2011
Table 7. Day 60 CV/Renal Rehospitalization or Death:
Multivariable Analysis
HR (95% CI)
P Value
Baseline troponin ⬎0.01*
1.23 (0.64, 2.35)
0.54
Baseline troponin ⬎0.03*
1.84 (1.04, 3.26)
0.04
Age of subject
1.00 (0.98, 1.03)
0.86
Male
1.13 (0.61, 2.08)
0.71
Baseline weight
0.99 (0.97, 1.01)
0.18
History of hypertension
0.66 (0.32, 1.36)
0.26
History of diabetes
1.38 (0.76, 2.50)
0.30
History of asthma, bronchitis, or COPD
1.20 (0.66, 2.18)
0.54
History of AF/flutter
1.02 (0.60, 1.72)
0.96
History of stroke, beyond 2 y
0.49 (0.15, 1.63)
0.25
History of ischemic heart disease
0.65 (0.36, 1.15)
0.14
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Systolic blood pressure
1.00 (0.99, 1.02)
0.78
Heart rate
1.01 (0.99, 1.03)
0.18
Screening BNP ⬎500 or NT proBNP ⬎2000
0.86 (0.44, 1.71)
0.67
BUN
1.02 (1.00, 1.04)
0.07
Hemoglobin
0.91 (0.79, 1.05)
0.18
Sodium
0.94 (0.89, 1.00)
0.04
Day 1 creatinine value
1.08 (0.65, 1.81)
0.77
Randomized treatment
0.85 (0.67, 1.08)
0.19
AF indicates atrial fibrillation; BNP, brain natriuretic peptide; BUN, blood urea
nitrogen; CI, confidence interval; COPD, chronic obstructive pulmonary disease;
and HR, hazard ratio.
*Relative to negative troponin group. Models were run separately with
“baseline troponin ⬎0.01” and “baseline troponin ⬎0.03.” Because results for
other variables were very similar in the 2 models, only those for the model with
“baseline troponin ⬎0.01” are presented.
prognosis. Univariate analysis showed the same high event
rates in patients with positive and detectable cardiac troponin
T levels at baseline. In multivariate analysis, only positive
troponin T level was an independent predictor of mortality or
CV/renal rehospitalization at 60 days. Conversion to any
detectable level during hospitalization was also associated
with statistically significant higher event rates at 60 days.
There are several important findings of this analysis. First,
there was a high prevalence (60%) of baseline troponin T
elevation in this cohort. The reported prevalence has varied
widely in other trials and registries; however, direct comparisons are difficult due to differences in the population being
studied, different cutoff values, and variation in the assay
Figure 1. Day 60 cardiovascular (CV)/renal hospitalization or
death.
Figure 2. In-hospital (up to day 7) worsening heart failure (HF)
or death.
being used.7,8,17,18,21,25 Second, 8% of the total cohort of
patients (21% of those who were negative at baseline)
converted to detectable levels of troponin T by day 7 of
hospitalization. Finally, positive troponin T at baseline, and
conversion to positive levels, were associated with worse
outcomes at 60 days.
Cardiac troponin T is a marker of myocardial injury and
the prognostic significance of elevated troponin levels in the
evaluation and risk stratification of patients with AHF has
been demonstrated.11,17,26,27 Several studies have shown that
the release of troponin T is a predictor of short- and long-term
prognosis in patients with AHF.28 –32 In 84 872 subjects
hospitalized for AHF, Peacock et al analyzed in-hospital
outcomes and reported that a positive cardiac troponin was
associated with greater in-hospital mortality (95% CI, 2.24 –
2.89; P⬍0.001), a longer hospitalization, and greater use of
resources.7 In a large cohort of patients with stable chronic
HF from the Valsartan Heart Failure Trial (Val-HeFT),
detectable cardiac troponin T (⬎0.001 ng/mL) was found in
10.4% of 4053 patients and was associated with death (HR,
2.08; 95% CI, 1.72–2.52; P⬍0.001) and first hospitalization
for HF (HR, 1.55; 95% CI, 1.25–1.93; P⬍0.001).8 Other
studies in stable outpatients with HF have shown a significant
association between elevated levels of troponin and
outcomes.29
Of note is that there appeared to be similar risk of major
cardiac events between converters and the patients with
positive troponin T levels at baseline group. These elevations
probably reflect ongoing injury after admission.
Our results suggest that postadmission cTnT measurements
in addition to baseline measurements may be useful in
understanding patients who have an unfavorable hospital
course, particularly when those patients are initially troponin
negative. The association between troponin T release and
subsequent outcome suggests that myocardial injury occurs at
a modest but not inconsequential rate and may persist well
into the later stages of the hospitalization. Our study confirmed that the presence of troponin T at baseline and the
persistent release of troponin T are correlated with a poor
outcome.
Previous studies have shown the magnitude of troponin
elevation is correlated with the severity of HF and worse
outcomes.8,27–30 Indeed, in our study the magnitude of troponin T at baseline predicted worse long-term outcomes. This
evidence also suggests that a single measurement of cardiac
O’Connor et al
troponin T at baseline is a strong predictor of risk for
all-cause mortality and cardiovascular events, specifically
worsening of HF.
Clinical Implications
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Our study confirms that patients who present with positive
troponin T levels at baseline may have a worse prognosis.
Serial measurements may identify additional patients who
may be at risk. Troponin may be an emerging biomarker
useful for assessing safety and efficacy of HF therapies, and
the finding that serial troponin release occurs throughout the
hospitalization may provide a target for novel therapeutics to
mitigate the risk of morbidity and mortality. Our findings
suggest that myocardial injury is a frequent event in AHF
patients and the release of troponin, particularly as it relates to
current treatments and investigational therapies, should be
examined. It is yet to be seen whether the greater sensitivity
of new troponin assays will afford greater clinical utility in
predicting outcomes, given the fact that ⬎90% of acute
decompensated HF (ADHF) patients have detectable troponin
on these new assays.
Limitations
Our study was limited by the relatively modest number of
patients, short follow-up period, and modest number of
events. The small subgroup of patients with conversion from
negative to positive troponin T after admission is of particular
interest, but the association with poorer subsequent outcomes
must be viewed as hypothesis-generating rather than conclusive. In addition, the analysis was carried out as a post hoc
evaluation from the PROTECT pilot, of which the primary
objective was to evaluate the effects of rolofylline on outcome in AHF with renal impairment. There could be a risk of
overfitting the model, as the number of variables in the model
was based on the primary end point of the trial. Our findings
should be interpreted in the context of these limitations.
Conclusion
Our study confirms that troponin release is common in
patients with AHF and cardiorenal impairment and that
myocardial injury may continue to occur throughout hospitalization. In addition, our data show that positive troponin T
at baseline is associated with worse outcomes at 60 days and
conversion to any detectable level of troponin T may increase
60-day risk to the same extent as positive troponin T at
baseline. These findings suggest that serial troponin measurements may be useful in assessing the safety and efficacy of
existing and investigational therapies for AHF. Further prospective research is necessary to confirm these observations.
Sources of Funding
Statistical support was provided by Merck.
Disclosures
Drs O’Connor, Voors, Ponikowski, Dittrich, Metra, Teerlink,
Massie, Givertz, Cleland, Weatherley, and Cotter received research
funding from Merck. Drs Jia, Fujita, Mansoor, Bloomfield, and
DeLucca are employees of Merck.
Troponin Release and Outcomes in AHF Patients
731
References
1. Jessup M, Abraham WT, Casey DE, Feldman AM, Francis GS, Ganiats
TG, Konstam MA, Mancini DM, Rahko PS, Silver MA, Stevenson LW,
Yancy CW. 2009 Focused Update: ACCF/AHA Guidelines for the
Diagnosis and Management of Heart Failure in Adults: a report of the
American College of Cardiology Foundation/American Heart Association
Task Force on Practice Guidelines: developed in collaboration with the
International Society for Heart and Lung Transplantation. Circulation.
2009;119:1977–2016.
2. Harinstein ME, Filippatos GS, Gheorghiade M. Acute heart failure syndromes: epidemiology, risk stratification and prognostic factors. Acute
Card Care. 2009;11:77– 82.
3. Gheorghiade M, Pang PS. Acute heart failure syndromes. J Am Coll
Cardiol. 2009;53:557–573.
4. Cotter G, Felker GM, Adams KF, Milo-Cotter O, O’Connor CM. The
pathophysiology of acute heart failure: is it all about fluid accumulation.
Am Heart J. 2008;155:9 –18.
5. Summers RL, Amsterdam E. Pathophysiology of acute decompensated
heart failure. Heart Fail Clin. 2009;5:9 –17.
6. Perna ER, Macin SM, Canella JPC, Augier N, Stival JL, Cialzeta JR,
Pitzus AE, Garcia EH, Obregón R, Brizuela M, Barbagelata A. Ongoing
myocardial injury in stable severe heart failure: value of cardiac troponin
T monitoring for high-risk patient identification Circulation. 2004;110:
2376 –2382.
7. Peacock WF IV, De Marco T, Fonarow GC, Diercks D, Wynne J, Apple
FS, Wu AH; ADHERE Investigators. Cardiac troponin and outcome in
acute heart failure. N Engl J Med. 2008;358:2117–2126.
8. Latini R, Masson S, Anand IS, Diercks D, Wynne J, Apple FS, Wu AH;
ADHERE Investigators. Prognostic value of very low plasma concentrations of troponin T in patients with stable chronic heart failure.
Circulation. 2007;116:1242–1249.
9. Horwich TB, Patel J, MacLellan WR, Fonarow GC. Cardiac troponin I is
associated with impaired hemodynamics, progressive left ventricular dysfunction, and increased mortality rates in advanced heart failure. Circulation.
2003;108:833–838.
10. Abraham WT, Fonarow GC, Albert NM, Stough WG, Gheorghiade M,
Greenberg BH, O’Connor CM, Sun JL, Yancy CW, Young JB;
OPTIMIZE-HF Investigators and Coordinators. Predictors of in-hospital
mortality in patients hospitalized for heart failure: insights from the
Organized Program to Initiate Lifesaving Treatment in Hospitalized
Patients with Heart Failure (OPTIMIZE-HF). J Am Coll Cardiol. 2008;
52:347–356.
11. You JJ, Austin PC, Alter DA, Ko DT, Tu JV. Relation between cardiac
troponin I and mortality in acute decompensated heart failure. Am
Heart J. 2007;153:462– 470.
12. Hudson MP, O’Connor CM, Gattis WA, Tasissa G, Hasselblad V,
Holleman CM, Gaulden LH, Sedor F, Ohman EM. Implications of
elevated cardiac troponin T in ambulatory patients with heart failure: a
prospective analysis. Am Heart J. 2004;147:546 –552.
13. Katus HA, Remppis A, Scheffold T, Diederich KW, Kuebler W. Intracellular compartmentation of cardiac troponin T and its release kinetics in
patients with reperfused and nonreperfused myocardial infarction. Am J
Cardiol. 1991;67:1360 –1367.
14. Davies CH, Harding SE, Poole-Wilson PA. Cellular mechanisms of
contractile dysfunction in human heart failure. Eur Heart J. 1996;17:
189 –198.
15. Del Carlo CH, O’Connor CM. Cardiac troponins in congestive heart
failure. Am Heart J. 1999;138:646 – 653.
16. Felker GM, Benza RL, Chandler AB, Leimberger JD, Cuffe MS, Califf
RM, Gheorghiade M, O’Connor CM; OPTIME-CHF Investigators. Heart
failure etiology and response to milrinone in decompensated heart failure:
results from the OPTIME-CHF study. J Am Coll Cardiol. 2003;41:
997–1003.
17. Metra M, Nodari S, Parrinello G, Specchia C, Brentana L, Rocca P,
Fracassi F, Bordonali T, Milani P, Danesi R, Verzura G, Chiari E, Dei
Cas L. The role of plasma biomarkers in acute heart failure: serial changes
and independent prognostic value of NT-proBNP and cardiac troponin-T.
Eur J Heart Fail. 2007;9:776 –786.
18. Gheorghiade M, Gattis Stough W, Adams KF Jr, Jaffe AS, Hasselblad V,
O’Connor CM. The Pilot Randomized Study of Nesiritide Versus Dobutamine in Heart Failure (PRESERVD-HF). Am J Cardiol. 2005;96:18G–25G.
19. Cotter G, Dittrich HC, Davison Weatherley B, Bloomfield DM,
O’Connor CM, Metra M, Massie BM; Protect Steering Committee, Investigators, and Coordinators. The PROTECT pilot study: a randomized,
placebo-controlled, dose-finding study of the adenosine A1 receptor an-
732
20.
21.
22.
Downloaded from http://circheartfailure.ahajournals.org/ by guest on May 2, 2017
23.
24.
25.
Circ Heart Fail
November 2011
tagonist rolofylline in patients with acute heart failure and renal
impairment. J Card Fail. 2008;14:631– 640.
Rhodes PJ, Rhodes RS, McClelland GH, Culbertson VL, Jahnigen DW,
Bloedow DC. Evaluation of eight methods for estimating creatinine
clearance in men. Clin Pharm. 1987;6:399 – 406.
Adams KF Jr, Fonarow GC, Emerman CL, LeJemtel TH, Costanzo MR,
Abraham WT, Berkowitz RL, Galvao M, Horton DP; ADHERE Scientific Advisory Committee and Investigators. Characteristics and
outcomes of patients hospitalized for heart failure in the United States:
rationale, design, and preliminary observations from the first 100,000
cases in the Acute Decompensated Heart Failure National Registry
(ADHERE). Am Heart J. 2005;149:209 –216.
Dickstein K, Cohen-Solal A, Filippatos G, McMurray JJ, Ponikowski P,
Poole-Wilson PA, Strömberg A, van Veldhuisen DJ, Atar D, Hoes AW,
Keren A, Mebazaa A, Nieminen M, Priori SG, Swedberg K; ESC Committee for Practice Guidelines (CPG). ESC Guidelines for the diagnosis
and treatment of acute and chronic heart failure 2008: the Task Force for
the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of
the European Society of Cardiology: developed in collaboration with the
Heart Failure Association of the ESC (HFA) and endorsed by the
European Society of Intensive Care Medicine (ESICM). Eur J Heart Fail.
2008;10:933–989.
Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG,
Jessup M, Konstam MA, Mancini DM, Michl K, Oates JA, Rahko PS, Silver
MA, Stevenson LW, Yancy CW. 2009 focused update incorporated into the
ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart
Failure in Adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines:
developed in collaboration with the International Society for Heart and Lung
Transplantation. Circulation. 2009;119:e391–e479.
Safran N, Shneyvays V, Balas N, Jacobson KA, Nawrath H, Shainberg A.
Cardioprotective effects of adenosine A1 and A3 receptor activation
during hypoxia in isolated rat cardiac myocytes. Mol Cell Biochem.
2001;217:143–152.
Fonarow GC, Abraham WT, Albert NM, Stough WG, Gheorghiade M,
Greenberg BH, O’Connor CM, Sun JL, Yancy CW, Young JB;
26.
27.
28.
29.
30.
31.
32.
OPTIMIZE-HF Investigators and Coordinators. Prospective evaluation of
beta-blocker use at the time of hospital discharge as a heart failure
performance measure: results from OPTIMIZE-HF. J Card Fail. 2007;
13:722–731.
Fonarow GC, Peacock WF, Horwich TB, Phillips CO, Givertz MM,
Lopatin M, Wynne J; ADHERE Scientific Advisory Committee and
Investigators. Usefulness of B-type natriuretic peptide and cardiac
troponin levels to predict in-hospital mortality from ADHERE. Am J
Cardiol. 2008;101:231–237.
Perna ER, Macín SM, Cimbaro Canella JP, Alvarenga PM, Ríos NG,
Pantich R, Augier N, Farías EF, Jantus E, Brizuela M, Medina F. Minor
myocardial damage detected by troponin T is a powerful predictor of
long-term prognosis in patients with acute decompensated heart failure.
Int J Cardiol. 2005;99:253–261.
Demir M, Kanadasi M, Akpinar O, Dönmez Y, Avkarogullari M, Alhan
C, Inal T, San M, Usal A, Demirtas M. Cardiac troponin T as a prognostic
marker in patients with heart failure: a 3-year outcome study. Angiology.
2007;58:603– 609.
Miller WL, Hartman KA, Burritt MF, Grill DE, Jaffe AS. Profiles of
serial changes in cardiac troponin T concentrations and outcome in
ambulatory patients with chronic heart failure. J Am Coll Cardiol. 2009;
54:1715–1721.
Perna ER, Macín SM, Parras JI, Pantich R, Farías EF, Badaracco JR,
Jantus E, Medina F, Brizuela M. Cardiac troponin T levels are associated
with poor short- and long-term prognosis in patients with acute cardiogenic pulmonary edema. Am Heart J. 2002;143:814 – 820.
Sato Y, Yamada T, Taniguchi R, Nagai K, Makiyama T, Okada H,
Kataoka K, Ito H, Matsumori A, Sasayama S, Takatsu Y. Persistently
increased serum concentrations of cardiac troponin T in patients with
idiopathic dilated cardiomyopathy are predictive of adverse outcomes.
Circulation. 2001;103:369 –374.
Gheorghiade M, Gattis Stough W, Adams JKF, Jaffe AS, Hasselblad V,
O’Connor CM. The Pilot Randomized Study of Nesiritide Versus Dobutamine in Heart Failure (PRESERVD-HF). Am J Coll Cardiol.
2005;96:18 –25.
CLINICAL PERSPECTIVE
Heart failure continues to be a major health burden, with a high incidence of acute hospital admission. One of the
limitations of broad-based therapies in the patients with acute decompensated heart failure is the heterogeneity of patients
presenting with this syndrome. Traditional risk factor prediction models have only limited accuracy in this population to
identify those at highest risk for worsening outcomes. A growing body of evidence suggests that measurement of troponin
levels proves an accurate predictor of deterioration in heart failure. However, few studies have looked at the serial trend
of troponin release in these patients. In our study, we evaluated the incidence of troponin release during heart failure
hospitalization and the relationship of troponin release with outcomes. Serial measurements were used to determine
whether patients who had a conversion from a troponin negative measurement to a detectable level had adverse outcomes
similar to those presenting with an elevation of troponin at baseline. Measurements were collected at randomization and
days 2, 3, 4, and 7. The study included 288 patients and showed a high incidence of baseline cardiac troponin T elevation
in this cohort; 21% of those negative at baseline converted to detectable levels by day 7. Positive troponin at baseline and
conversion to positive levels were associated with worse outcomes at 60 days. Thus, the findings from this study suggest
that serial measurements of troponin should be considered in the evaluation of patients with acute decompensated heart
failure and that these findings should be confirmed in a large, prospective study.
Downloaded from http://circheartfailure.ahajournals.org/ by guest on May 2, 2017
Impact of Serial Troponin Release on Outcomes in Patients With Acute Heart Failure:
Analysis From the PROTECT Pilot Study
Christopher M. O'Connor, Mona Fiuzat, Carlo Lombardi, Kenji Fujita, Gang Jia, Beth A.
Davison, John Cleland, Daniel Bloomfield, Howard C. Dittrich, Paul DeLucca, Michael M.
Givertz, George Mansoor, Piotr Ponikowski, John R. Teerlink, Adriaan A. Voors, Barry M.
Massie, Gad Cotter and Marco Metra
Circ Heart Fail. 2011;4:724-732; originally published online September 6, 2011;
doi: 10.1161/CIRCHEARTFAILURE.111.961581
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