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JACC: Heart Failure

 2014 by the American College of Cardiology Foundation


Published by Elsevier Inc.

Vol. 2, No. 1, 2014


ISSN 2213-1779/$36.00
http://dx.doi.org/10.1016/j.jchf.2013.10.004

MINI FOCUS ISSUE: PHYSICAL EXAM

Prognostic Value of the Physical Examination


in Patients With Heart Failure and
Atrial Fibrillation
Insights From the AF-CHF Trial
(Atrial Fibrillation and Chronic Heart Failure)
Guillem Caldentey, MD,* Paul Khairy, MD, PHD,*y Denis Roy, MD,* Hugues Leduc, MSC,y
Mario Talajic, MD,* Normand Racine, MD,* Michel White, MD,* Eileen OMeara, MD,*
Marie-Claude Guertin, PHD,y Jean L. Rouleau, MD,* Anique Ducharme, MD, MSC*
Montreal, Quebec, Canada
Objectives

This study sought to assess the prognostic value of physical examination in a modern treated heart failure
population.

Background

The physical examination is the cornerstone of the evaluation and monitoring of patients with heart failure. Yet, the
prognostic value of congestive signs (i.e., peripheral edema, jugular venous distension, a third heart sound, and
pulmonary rales) has not been assessed in the current era.

Methods

A post-hoc analysis was conducted on all 1,376 patients, 81% male, mean age 67  11 years, with symptomatic
left ventricular systolic dysfunction enrolled in the AF-CHF (Atrial Fibrillation and Congestive Heart Failure) trial. The
prognostic value of baseline physical examination ndings was assessed in univariate and multivariate Cox
regression analyses.

Results

Peripheral edema was observed in 425 (30.9%), jugular venous distension in 297 (21.6%), a third heart sound in
207 (15.0%), and pulmonary rales in 178 (12.9%) patients. Death from cardiovascular causes occurred in 357
(25.9%) patients over a mean follow-up of 37  19 months. All 4 physical examination ndings were associated
with cardiovascular mortality in univariate analyses (all p values <0.01). In multivariate analyses, taking all 4 signs
as potential covariates, only rales (hazard ratio 1.41; 95% condence interval: 1.07 to 1.86; p 0.013) and
peripheral edema (hazard ratio: 1.25; 95% condence interval: 1.00 to 1.57; p 0.048) were associated with
cardiovascular mortality, independent of other variables.

Conclusions

In the modern era, congestive signs on the physical examination (i.e., peripheral edema, jugular venous distension,
a third heart sound, and pulmonary rales) continue to provide important prognostic information in patients with
congestive heart failure. (J Am Coll Cardiol HF 2014;2:1523) 2014 by the American College of Cardiology
Foundation

Heart failure is considered a major epidemic of the modern


era. It is associated with substantial morbidity, mortality,
and healthcare resource utilization. Demographic trends

From the *Montreal Heart Institute, Universit de Montral, Montreal, Quebec,


Canada; and the yMontreal Heart Institute Coordinating Center, Montreal, Quebec,
Canada. The AF-CHF trial was funded by the Canadian Institutes of Health
Research (MCT-41552). Dr. Ducharme holds a senior research grant from le Fond
de Recherche du Qubec en Sant (FRQS). Dr. White holds the Caroline and
Richard Renault Chair in Heart Failure of the Montreal Heart Institute. Dr. Khairy is
supported by a Canada Research Chair in Electrophysiology and Adult Congenital
Heart Disease. Dr. Caldentey holds a fellowship grant from the Spanish Society of
Cardiology. All other authors have reported that they have no relationships relevant to
the contents of this paper to disclose.
Manuscript received August 6, 2013; revised manuscript received October 1, 2013,
accepted October 3, 2013.

suggest that the prevalence of heart failure will continue to


rise with the aging population. In patients with chronic heart
failure (CHF) due to systolic dysfunction, several factors
associated with a poorer prognosis have been identied,
including functional parameters (13), echocardiographic
(46) and electrocardiographic (7) indices, and serum biomarkers (812).
See page 32

The value of a careful and thorough physical examination


has come into question in an age when detailed imaging
studies and ancillary testing are readily available (13,14).
Prior publications from studies performed some decades

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16

Caldentey et al.
Physical Examination and Heart Failure

ago, when pharmacological management reected knowledge of


the time, supported the prognostic
ACE = angiotensinrole of congestive signs. It remains
converting enzyme
to be demonstrated whether such
ARB = angiotensin receptor
ndings may be generalized to
blocker
patients with CHF on optimal
CHF = chronic heart failure
medical therapy according to
CI = condence interval
current standards. Moreover, the
HR = hazard ratio
continued relevance of physical
LVEF = left ventricular
signs in a population of patients
ejection fraction
with atrial brillation has not
NYHA = New York Heart
previously been addressed. We,
Association
therefore, assessed the prognostic
value of 4 physical examination ndings (i.e., peripheral
edema, jugular venous distension, a third heart sound, and
pulmonary rales) in a contemporary cohort of patients with left
ventricular systolic dysfunction and a history of nonpermanent
atrial brillation.
Abbreviations
and Acronyms

Methods
Study population. A post-hoc analysis was conducted on all
patients enrolled in the AF-CHF (Atrial Fibrillation
and Congestive Heart Failure) trial. The study protocol has
been previously described (15). Briey, the AF-CHF trial was
an international multicenter trial sponsored by the Canadian
Institutes of Health Research that enrolled 1,376 patients
between May 2001 and June 2005 with CHF and nonpermanent atrial brillation. Patients were required to have a
left ventricular ejection fraction (LVEF) 35%, and New
York Heart Association (NYHA) functional class II to IV
symptoms within 6 months of randomization, or functional
class I symptoms if the LVEF was 25% or if the patient was
hospitalized for CHF in the previous 6 months. Patients were
randomized 1:1 to rhythm- or rate-control treatment strategies for atrial brillation. No treatment differences were
observed with respect to the primary outcome (i.e., cardiovascular mortality) and main secondary outcomes (e.g., allcause mortality, heart failurerelated hospitalization, stroke,
quality of life). The study protocol was approved by each
participating centers institutional review board and all patients provided written informed consent.
Pharmacological therapy. The maximum tolerated dose of
beta-blockers (i.e., carvedilol, bisoprolol, or metoprolol) and
angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB) was recommended in all
patients. In addition, spironolactone was recommended in
patients on loop diuretics with NYHA functional class III
or IV symptoms. Patients randomized to rhythm-control
received amiodarone as the initial antiarrhythmic drug.
Targeted heart rates for rate-control were <80 beats/min at
rest and <110 beats/min during 6-min walk tests. Anticoagulation was recommended in both treatment arms.
Baseline variables and physical examination. A baseline
physical examination was performed by local site

JACC: Heart Failure Vol. 2, No. 1, 2014


February 2014:1523

investigators and included an assessment for peripheral


edema (none, mild [1] or marked [2]; dichotomized as
present [1] or absent), jugular venous distension (present
or absent), a third heart sound (present or absent), and rales
on pulmonary auscultation (present or absent). Additional
baseline variables collected included patient demographics
(e.g., age at randomization, ethnic background, sex, body
mass index), type of heart disease, comorbidities (e.g., coronary artery disease, hypertension, diabetes, stroke or transient ischemic attacks), pharmacological therapy (e.g., ACE
inhibitors, ARBs, beta-blockers, diuretics, lipid lowering
drugs, digoxin, calcium channel blockers, and oral anticoagulants), echocardiographic parameters (e.g., left atrial size,
LVEF, mitral regurgitation grade), electrocardiographic
indices (e.g., heart rate, QRS duration, QTc), serum markers
(e.g., electrolytes, creatinine, complete blood count), NYHA
functional class (I to II vs. III to IV), baseline rhythm, and
randomized treatment arm (rate vs. rhythm control).
Cardiovascular outcomes. Patients were followed at
3 weeks, 4 months, every 4 months until 4 years, and then
biannually until 6 years. As in the main trial, the primary
outcome for the current study was cardiovascular mortality.
Secondary outcomes included all-cause mortality, heart
failurerelated mortality, sudden cardiac death, and heart
failurerelated hospitalization. All events were classied by
an independent adjudicating committee blinded to the
treatment assignment.
Statistical analysis. Continuous variables are summarized
by mean  SD. Categorical variables are represented by
frequencies and percentages. Two-group baseline comparisons were performed by Student t or chi-square tests where
appropriate. Event-free survival for mortality and hospitalization outcomes was plotted using the Kaplan-Meier
method, with comparisons by log-rank statistics. Time
0 was dened as the time of physical examination. Univariate and multivariate Cox regression models were created
for each outcome variable (i.e., cardiovascular mortality, allcause mortality, heart failurerelated death, sudden cardiac
death, and heart failurerelated hospitalization). The covariates considered in the multivariate regression models are
listed in Table 1.
Two approaches to multivariate modeling were used. The
rst consisted of building separate multivariate models for
each congestive sign, with the congestive sign of interest
forced in the model. The second approach considered all 4
congestive signs as potential covariates within a single
multivariate model. With both approaches, randomization
to rate- versus rhythm-control therapy was forced into the
model. Other baseline covariates that were signicant at the
0.2 level in univariate analyses were included in stepwise
multivariate Cox regression models. To account for missing
data, a multiple imputation analysis was performed as the
main approach, with a secondary complete-case approach
as a sensitivity analysis. Given that the 2 approaches yielded
similar results, data from the main approach are presented.
Imputed data sets were generated using IVEware version

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Baseline Characteristics According to the Presence or Absence of Congestive Signs on the Physical Examination
Peripheral Edema

Jugular Venous Distension

All Patients
(N 1,376)

Present*
(n 425)

Absent
(n 949)

p Value

Present
(n 297)

Absent
(n 1,072)

Age, yrs

66.7  11.1

68.5  10.0

66.0  11.4

<0.0001

68.3  10.0

66.4  11.3

Male gender

1,118 (81.3)

322 (75.8)

800 (84.3)

0.0002

235 (79.1)

883 (82.4)

25 (1.8)

9 (2.1)

16 (1.7)

0.5800

6 (2.0)

19 (1.7)

Ischemic heart disease

718 (52.2)

244 (57.4)

474 (50.0)

0.0105

175 (59.0)

Diabetes mellitus

283 (20.6)

118 (27.8)

164 (17.3)

<0.0001

66 (22.2)

Hypertension

656 (47.7)

233 (54.8)

421 (44.4)

0.0003

149 (50.2)

501 (46.7)

Myocardial infarction

586 (42.6)

193 (45.4)

393 (41.4)

0.1659

141 (47.5)

443 (41.3)

TIA/stroke/bleeding

124 (9.0)

32 (7.5)

92 (9.7)

0.1955

26 (8.7)

98 (9.1)

NYHA functional
class III to IV

431 (31.3)

200 (47.1)

231 (24.3)

<0.0001

158 (53.2)

272 (25.4)

Systolic blood pressure,


mm Hg

119  19

116  20

120  19

0.0016

117  21

119  19

Heart rate,
beats/min

78  19

80  19

77  19

0.0005

80  20

Left ventricular
ejection fraction, %

26.9  6.0

26.9  5.8

26.8  6.1

0.7011

QRS width, ms

113  30

116  32

113  28

Sodium, mmol/l

139  4

139  4

139  4

Creatinine, mmol/l

112  41

118  42

110  40

0.0002

Atrial brillation
at baseline

788 (57.3)

260 (61.2)

526 (55.5)

0.0488

AF history >6 months

292 (21.2)

78 (18.3)

214 (22.5)

Diuretics

1,124 (81.7)

375 (88.2)

Beta-blockers

1,085 (78.9)

330 (77.6)

ACE inhibitors

1,185 (86.1)

Aldosterone
antagonists

Third Heart Sound


Present
(n 207)

Absent
(n 1,166)

0.0048

68.3  10.7

66.5  11.1

0.2010

166 (80.2)

955 (81.9)

0.7778

4 (1.9)

21 (1.8)

540 (50.4)

0.0090

122 (58.9)

213 (19.9)

0.3731

37 (17.9)

0.2944

90 (43.5)

0.0579

107 (51.7)

0.8368
<0.0001

Pulmonary Rales
Present
(n 178)

Absent
(n 1,197)

p Value

0.0350

70.1  9.6

66.3  11.2

<0.0001

0.5579

137 (77.0)

986 (83.4)

0.0820

0.8964

3 (1.7)

22 (1.8)

0.8870

596 (51.1)

0.0379

107 (60.1)

611 (51.0)

0.0238

246 (21.1)

0.2907

34 (19.1)

249 (20.8)

0.6005

565 (48.5)

0.1864

99 (55.6)

556 (46.5)

0.0223

479 (41.1)

0.0045

85 (47.7)

501 (41.8)

0.1376

23 (11.1)

101 (8.7)

0.2573

19 (10.7)

105 (8.8)

0.4084

109 (52.7)

321 (27.5)

<0.0001

98 (55.1)

333 (27.8)

0.00455

114  19

120  19

<0.0001

77  19

0.0241

78  18

78  19

0.9000

26.1  6.2

27.1  5.9

0.0196

25.2  6.2

27.1  5.9

0.1182

116  30

113  30

0.2062

117  33

113  29

0.4395

140  4

139  4

0.3990

139  3

139  4

119  40

111  41

<0.0001

119  38

111  42

187 (63.0)

596 (55.6)

0.0242

122 (58.9)

0.0788

50 (16.8)

242 (22.6)

0.0326

747 (78.7)

<0.0001

262 (88.2)

856 (79.8)

753 (79.4)

0.4760

223 (75.1)

856 (79.8)

360 (84.7)

823 (86.7)

0.3179

263 (88.6)

616 (44.8)

219 (51.5)

396 (41.7)

0.0007

Digoxin

886 (64.4)

301 (70.8)

584 (61.5)

Amiodarone

559 (40.6)

166 (39.1)

393 (41.1)

97 (7.1)

20 (4.7)

77 (8.1)

p Value

p Value

Medical history

Black race

JACC: Heart Failure Vol. 2, No. 1, 2014


February 2014:1523

Table 1

Clinical characteristics
<0.0001

119  19

0.2532

83  22

77  19

0.0011

26.1  6.2

27.0  6.0

0.0625

0.0873

118  32

113  29

0.0600

0.6704

139  4

139  4

0.5936

0.0004

118  37

112  42

0.0087

663 (56.9)

0.5870

103 (57.9)

684 (57.2)

0.8652

51 (24.6)

241 (20.7)

0.1985

29 (16.3)

263 (22.0)

0.0839

0.0010

184 (88.9)

938 (80.5)

0.0038

158 (88.7)

965 (80.6)

0.0088

0.0752

161 (77.8)

921 (79.0)

0.6946

121 (68.0)

963 (80.5)

0.0001

917 (85.6)

0.1831

179 (86.5)

1004 (86.1)

0.8879

152 (85.4)

1,032 (86.2)

0.7673

157 (52.9)

457 (42.6)

0.0017

104 (50.2)

510 (43.7)

0.0829

89 (50.0)

526 (43.9)

0.1294

0.0009

203 (68.4)

680 (63.4)

0.1171

134 (64.7)

751 (64.4)

0.9280

129 (72.5)

757 (63.2)

0.0164

0.4118

118 (39.7)

439 (40.9)

0.7047

89 (43.0)

470 (40.3)

0.4685

78 (43.8)

481 (40.2)

0.3567

0.0226

21 (7.1)

76 (7.1)

0.9911

18 (8.7)

79 (6.8)

0.3204

9 (5.1)

88 (7.4)

0.2644

<0.0001

Treatment

ICD

Values are mean  SD or n (%). *Includes mild (1) or marked (2) peripheral edema.
ACE angiotensin-converting enzyme; AF atrial brillation; ICD implantable cardioverter-debrillator; NYHA New York Heart Association; TIA transient ischemic attack.

Caldentey et al.
Physical Examination and Heart Failure

117  20

17

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Caldentey et al.
Physical Examination and Heart Failure

0.0761

<0.0001

<0.0001

0.0004
290 (24.2)

134 (11.2)

94 (7.8)

362 (30.2)

p Valuey
Pulmonary Rales

287 (24.0)

0.1, a user-contributed implementation of sequential generalized regression techniques in SAS (SAS Institute, Cary,
North Carolina).
Two-tailed p values <0.05 were considered statistically
signicant. Statistical testing was performed using SAS
software Version 9.2 (SAS Institute).

<0.0001

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February 2014:1523

Absent
(n 1,197)

18

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57 (32.0)
0.0155
Values are n (%). Raw proportions are presented. *Includes mild (1) or marked (2) peripheral edema. yBased on log-rank tests comparing event-free survival.

282 (24.2)
64 (30.9)
0.0008
254 (23.7)
89 (30.0)
0.1442
237 (25.0)
109 (25.6)
Heart failurerelated hospitalization

25 (14.0)
0.1557
130 (11.1)
29 (14.0)
0.1571
119 (11.1)
38 (12.8)
0.0160
58 (13.6)
Sudden cardiac death

101 (10.6)

83 (46.6)

36 (20.2)
0.0149

0.0020
359 (30.8)

102 (8.7)
28 (13.5)

86 (41.5)
<0.0001

<0.0001
43 (14.5)

86 (8.0)

119 (40.1)
<0.0001

67 (7.1)
62 (14.6)

174 (40.9)

Heart failurerelated death

All-cause mortality

270 (28.4)

<0.0001

323 (30.1)

70 (39.3)
0.0035
287 (24.6)
70 (33.8)
0.0004
96 (32.3)
139 (32.7)
Cardiovascular mortality

217 (22.9)

<0.0001

258 (24.1)

p Valuey
Absent
(n 1,166)
Present
(n 297)
Present*
(n 425)

Absent
(n 949)

p Valuey

Absent
(n 1,072)

p Valuey

Present
(n 207)

Third Heart Sound


Jugular Venous Distension
Peripheral Edema

Mortality and Hospitalization Outcomes According to the Presence or Absence of Congestive Signs on the Physical Examination
Table 2

Baseline characteristics. A total of 1,376 patients, mean


age 67  11 years, 81% male, were enrolled. Data on
peripheral edema was available in 1,374 (99.9%), jugular
venous distension in 1,369 (99.5%), a third heart sound
in 1,373 (99.8%), and pulmonary rales in 1,375 (99.9%)
patients. Complete data on all 4 congestive signs were
available in 1,369 (99.5%) patients. The incidence of peripheral edema was 30.9%, jugular venous distension 21.7%,
a third heart sound 15.0%, and pulmonary rales 13.0%,
with no differences between rhythm- versus rate-control
treatment strategies. Baseline characteristics in all patients
and according to whether they had positive ndings on
physical examination are summarized in Table 1. In general,
patients with congestive signs were older, had higher serum
creatinine levels, faster heart rates, and were more likely to
have ischemic heart disease and markers of advanced heart
failure such as NYHA functional class III or IV symptoms
and diuretic therapy. Atrial brillation at baseline, hypertension, and digoxin use were more common among patients
with peripheral edema and/or rales. Patients with rales were
less likely to be treated with beta-blockers.
Prevalence of cardiovascular outcomes. Over a mean
follow-up of 37  19 months, 445 (32.3%) patients died
and 347 (25.2%) required at least 1 hospitalization for heart
failure. Cardiovascular mortality accounted for 357 (80.2%)
deaths, which were subclassied as sudden cardiac death
of presumed arrhythmic etiology in 159 and heart failure
related in 130 patients. The prevalence of each cardiovascular outcome is summarized in Table 2 according to
whether or not congestive signs were present on physical examination. Freedom from cardiovascular mortality is
plotted in Figure 1 according to the presence or absence of
jugular venous distension (Fig. 1A), peripheral edema
(Fig. 1B), pulmonary rales (Fig. 1C), and a third heart
sound (Fig. 1D). Cardiovascular outcomes according to
whether patients had at least 1 positive congestive sign are
plotted in Figure 2.
Cardiovascular outcomes associated with each physical
sign separately. In univariate analyses, peripheral edema
(hazard ratio [HR]: 1.648, 95% condence interval [CI]:
1.331 to 2.039), p <0.0001), jugular venous distension (HR:
1.518, 95% CI: 1.201 to 1.920), p 0.0005), a third heart
sound (HR: 1.473, 95% CI: 1.134 to 1.913), p 0.0037),
and pulmonary rales (HR: 1.923, 95% CI: 1.480 to 2.497),
p <0.0001) were all associated with increased risk of cardiovascular mortality. Table 3 summarizes the univariate and
multivariate hazard ratios for all cardiovascular outcomes

Present
(n 178)

Results

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February 2014:1523

Figure 1

Caldentey et al.
Physical Examination and Heart Failure

19

Kaplan-Meier Estimates of Death From Cardiovascular Causes (Primary Outcome)

Kaplan-Meier analysis of event-free survival for the primary endpoint (cardiovascular mortality) according to the presence (red) or absence (blue) of elevated jugular venous
pressure (A), peripheral edema (B), rales (C), and third heart sound (D). Comparisons were performed by log-rank tests.

associated with each congestive sign considered separately.


In addition to cardiovascular mortality, peripheral edema
was independently associated with all-cause mortality and
heart failurerelated death. Jugular venous distension was
independently associated with heart failurerelated mortality
but not the other outcomes. No cardiovascular outcome
was independently predicted by the presence of a third heart
sound. In contrast, pulmonary rales was independently
associated with all mortality outcomes except sudden death.
In addition, pulmonary rales was the only congestive sign
independently associated with heart failurerelated
hospitalization.
Multivariate models with all 4 physical signs. In multivariate analyses that included all 4 congestive signs as
potential covariates, peripheral edema (HR: 1.25; 95% CI:
1.00 to 1.57; p 0.0482) and pulmonary rales (HR: 1.41;
95% CI: 1.08 to 1.86; p 0.0133) remained independent
predictors of cardiovascular mortality. Other factors independently associated with cardiovascular mortality were
older age (HR: 1.019 per year; 95% CI: 1.008 to 1.031;
p 0.0007), lower systolic blood pressure (HR: 0.992 per
mm Hg; 95% CI: 0.986 to 0.998; p 0.0105), higher

serum creatinine level (HR: 1.003 per mmol/l; 95% CI:


1.001 to 1.005; p 0.0003), NYHA functional class III or
IV symptoms (HR: 1.30; 95% CI: 1.04 to 1.62; p
0.0234), ischemic heart disease (HR: 1.75; 95% CI: 1.39 to
2.21; p < 0.0001), diuretics (HR: 1.49; 95% CI: 1.06 to
2.10; p 0.0212), and aldosterone antagonists (HR: 1.39;
95% CI: 1.11 to 1.72; p 0.0034).
Peripheral edema was independently associated with allcause mortality and heart failurerelated death. Pulmonary
rales was independently associated with heart failurerelated
death and hospitalization. No cardiovascular outcome was
independently predicted by jugular venous distension or
presence of a third heart sound.
Discussion
Sophisticated laboratory techniques provide the contemporary clinician with a wealth of diagnostic and prognostic
information that calls into question the residual value of a
thoughtful physical examination. Our analyses in this
cohort of patients with CHF and history of atrial brillation
suggest that each of the 4 congestive signs on physical

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20

Figure 2

Caldentey et al.
Physical Examination and Heart Failure

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February 2014:1523

Kaplan-Meier Estimates of Secondary Outcomes, in Patients With at Least 1 Positive Congestive Sign on
Physical Examination Versus None

Freedom from cardiovascular mortality (A), all-cause mortality (B), heart failurerelated death (C), and heart failurerelated hospitalization (D) are plotted in patients with at
least 1 positive congestive sign on the physical examination (red) versus none (blue). Comparisons were performed by log-rank tests.

examination continue to provide relevant prognostic information. Peripheral edema, jugular venous distension, a third
heart sound, and pulmonary edema were each associated
with increased cardiovascular mortality, all-cause mortality,
and heart failurerelated death. In addition, peripheral
edema was signicantly associated with sudden cardiac
death, and jugular venous distension, a third heart sound,
and pulmonary edema with heart failurerelated hospitalizations. In multivariate analyses that included standard
clinical, electrocardiographic, and echocardiographic parameters: 1) peripheral edema and pulmonary rales remained
independent predictors of all-cause and cardiovascular
mortality, associated with a 2-fold increased risk of heart
failurerelated death; 2) pulmonary rales independently
predicted hospitalizations for heart failure; and 3) jugular
venous distension was associated with a 48% increased risk
of heart failurerelated death.
The few studies that addressed the prognostic value of
congestive signs in the setting of acute heart failure have
yielded consistent results (16,17). The presence of an S3
has been associated with mortality in patients listed for

heart transplantation (18). In patients recently hospitalized


with decompensated heart failure and NYHA functional
class IV symptoms, the absence of any congestive sign
(dened by jugular venous distension, edema, orthopnea,
weight gain, or need for increased diuretic dose) was
associated with superior 2-year survival (19). Conversely,
rales or peripheral edema 1 week after hospital discharge
predicted adverse cardiovascular outcomes at 1 year of
follow-up (20). A post-hoc analysis of the EVEREST
(Efcacy of Vasopressin Antagonism in Heart Failure
Outcome Study With Tolvaptan) found that patients with
a higher composite congestion score experienced high
mortality and readmission rates (21).
The prognostic value of the physical examination in the
outpatient setting, as performed in the current study, is
more controversial. A retrospective analysis of the SOLVD
(Studies Of Left Ventricular Dysfunction) reported that
jugular venous distension and a third heart sound were
associated with increased cardiovascular mortality (22); the
presence of peripheral edema and rales was not assessed.
Moreover, this analysis was based on a population enrolled

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0.721.16
0.91

Heart failurerelated hospitalization

The primary analysis was adjusted for the following baseline variables: age, sex, left ventricular ejection fraction, New York Heart Association functional class, the presence or absence of diabetes or hypertension, the use or nonuse of an internal debrillator, the time since the
diagnosis of atrial brillation, the creatinine level, and the use or nonuse of a beta-blocker, angiotensin-converting enzyme inhibitor, or oral anticoagulant. Signicant p values are in bold.
CI condence interval.

0.3307

0.0211
1.051.90
1.42

0.0003

0.991.90
1.37

Sudden cardiac death

0.4557

1.22

0.951.58

0.1208

1.11

0.841.48

0.4735

0.801.92
1.24
0.6871
0.721.64
1.09
0.3517
0.831.71
1.19

0.0286

1.402.85
1.99

0.0584

1.423.17
2.12
0.9902
0.641.54
1.00
0.0458
1.012.17
1.48

0.0097

Heart failurerelated death

0.0001

1.031.69

1.091.88
1.43

1.32
0.4695

0.4489
0.851.46

0.861.39
1.09

1.11
0.1406

0.1387
0.951.47

0.941.54
1.20

1.18
0.0055
1.091.61
1.32

All-cause mortality

0.0130
1.061.65
1.32

Cardiovascular mortality

0.941.48
1.18

Heart failurerelated hospitalization

Multivariate analyses

0.0773

0.0004
1.252.21
1.67
0.0160
1.061.84
1.40
1.181.93

<0.0001

1.082.05
1.49

0.1432

1.51

0.0010

0.962.25
1.47
0.1580
0.892.00
1.34
0.1415
0.911.89
1.31

<0.0001

Sudden cardiac death

0.0165

2.054.43
3.02
0.0165
1.102.54
1.67
0.0002
2.03
1.683.35
2.37

Heart failurerelated death

<0.0001

1.412.92

1.432.31

1.482.50
1.92

1.82
0.0023

0.0040
1.131.91

1.141.83
1.44

1.47

1.51
1.372.01
1.66

1.52
1.332.03
1.64

All-cause mortality

<0.0001

Caldentey et al.
Physical Examination and Heart Failure

Cardiovascular mortality

<0.0001

1.211.93

0.0004

p Value
95% CI
Hazard ratio
p Value
95% CI
Hazard ratio
Univariate analyses

0.0001

p Value
95% CI
Hazard ratio

Third Heart Sound


Jugular Venous Distension
Peripheral Edema

Univariate and Multivariate Hazard Ratios for the Congestive Signs on Physical Examination
Table 3

1.221.86

95% CI
Hazard ratio

Pulmonary Rales

p Value

<0.0001

JACC: Heart Failure Vol. 2, No. 1, 2014


February 2014:1523

21

over 25 years ago in whom less than 10% received betablockers, ACE inhibitors were randomly allocated, and 9%
were treated with potassium sparing diuretics. In contrast, a
substudy from the Digitalis Investigator Group created a
global congestion score that combined the 4 physical examination signs assessed in our study along with symptoms
and radiological ndings (23). This score independently
predicted mortality at 36 months in patients with systolic
dysfunction on ACE inhibitors. Because the individual
contribution of physical signs was not independently
analyzed, the prognostic value of each cannot be surmised.
Moreover, concomitant use of beta-blockers and aldosterone
antagonists was not reported.
A community-based study reported that a combination
of right- and left-sided congestive signs predicted cardiovascular mortality in patients with CHF and preserved or
depressed left ventricular function (24). Analyses were
not specically conducted in the subgroup of patients
(45%) with left ventricular systolic dysfunction. Compared
to our study population, patients had less advanced heart
failure, as reected by a higher LVEF (34  6%) and
lower prevalence of congestive signs (e.g., rales 4%). Only
38% received an ACE inhibitor or ARB and 45% a betablocker. More recently, a retrospective analysis of 2,647
patients with NYHA functional class III to IV symptoms
enrolled in the CIBIS-II (Cardiac Insufciency Bisoprolol
Study-II) trial found that jugular venous distension
and ascites were independently associated with renal
dysfunction and all-cause mortality (25). Peripheral edema
and jugular venous distension were also associated with
heart failure deaths and cardiovascular hospitalizations.
Importantly, the prognostic value of pulmonary rales was
not assessed. As in other studies, beta-blockers and aldosterone antagonists were underprescribed according to
current standards (50% and 10% of the population, respectively) (25).
In our more contemporary patient population, 86%
received ACE inhibitors, 79% beta-blockers, and 45%
aldosterone antagonists. All 4 congestive signs (i.e., peripheral edema, jugular venous distension, the presence of a
third heart sound, and pulmonary rales) were associated with
increased cardiovascular mortality. Interestingly, physical
examination ndings associated with edema (i.e., peripheral
edema and pulmonary rales) remained more powerful independent predictors of cardiovascular outcomes than jugular
venous distension and a third heart sound. Increased
hydrostatic pressure in right heart cavities is transmitted to
systemic veins and capillaries, leading to venous congestion
(including jugular distension), peripheral edema, and/or
ascites. While increased central venous pressures by catheterization have been associated with worsening renal function and prognosis in patients with CHF (2628), jugular
venous distension on physical examination frequently underestimates right atrial pressures (29). In contrast, peripheral edema may be considered a more advanced marker of
heart failure in that it represents the inability of the

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22

Caldentey et al.
Physical Examination and Heart Failure

cardiovascular system to tolerate the increase in intravascular


pressure once venous compliance has been exceeded.
On the left side of the circulation, elevated lling pressures have been associated with adverse outcomes in patients
with CHF (18,30,31). The sympathetic nervous system is
activated as result of myocardial stretch (32) and increased
left atrial pressures are transmitted to the pulmonary venous
system (33). The capillary barrier responds to chronic increases in pressure by reducing its permeability, with
consequent interstitial edema. In advanced heart failure,
compensatory mechanisms are overwhelmed, resulting in
pulmonary congestion and rales on physical examination.
In contrast, a third heart sound, which occurs in
early diastole during the rapid left ventricular lling phase,
reects increased left ventricular lling pressures and
decreased compliance (34,35). It has been associated with
mortality in patients listed for heart transplantation (18).
However, concerns have been raised over reliability and
interobserver agreement (3638). In addition, of all the
physical signs assessed in our study population, it may be
the most likely to be confounded by irregular heart rates in
atrial brillation. Moreover, a poor correlation between a
third heart sound and lling pressures by catheterization
has been reported (39). The observed lack of independent
association between a third heart sound and cardiovascular
outcomes in our study may reect these observations.
Study limitations. The study is retrospective and subject to
limitations inherent to observational research. While analyses control for baseline imbalances and potential confounders, they cannot adjust for unknown or unmeasured
variables. Outcome variables were subject to standardized
denitions and adjudicated by a blinded committee of experts. In contrast, the physical examination was performed
without investigator blinding or independent adjudication.
As such, ndings may be inuenced by extraneous factors
such as clinical acumen and knowledge of the patients
medical chart. Nevertheless, the physical examination reects standard clinical practice in an adult population.
Finally, while our analyses controlled for underlying rhythm
at the time of assessment, all patients had a history of
nonpermanent atrial brillation. As such, results may not be
generalizable to a patient population with a low prevalence
of atrial brillation.
Conclusions
In patients with CHF and a history of atrial brillation,
all 4 congestive signs on physical examination (peripheral
edema, jugular venous distension, the presence of a third
heart sound and pulmonary rales) were associated with an
increased risk of cardiovascular mortality. This increased
mortality was predominantly driven by an excess in heart
failurerelated deaths. In addition, congestive signs of edema
on physical examination (i.e., peripheral edema and pulmonary rales) independently predicted all-cause and cardiovascular mortality. The association between jugular

JACC: Heart Failure Vol. 2, No. 1, 2014


February 2014:1523

venous distension and heart failurerelated mortality was


likewise signicant but of lesser magnitude. Taken together,
these results suggest that the physical examination in modern times remains relevant in providing important prognostic information above and beyond standard clinical,
electrocardiographic, and echocardiographic parameters.
Reprint requests and correspondence: Dr. Anique Ducharme,
Montreal Heart Institute Research Center (Room S-2700), 5000,
Belanger East, Montreal (Quebec) H1T 1C8. Canada. E-mail:
anique.ducharme@umontreal.ca.

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Key Words: atrial brillation


examination.

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23

heart failure

outcomes

physical

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