Article, Cardiology

Long-term prognostic value of stress echocardiography in patients presenting to the ED with spontaneous chest pain

a b s t r a c t

Purpose: The aims of this study were to evaluate the long-term prognostic value of stress echocardiography (SE) in patients evaluated in emergency department (ED) and to determine SE parameters that best predicted outcome. Methods: Between June 2008 and July 2012, 626 patients with an episode of spontaneous chest pain underwent SE (exercise stress echocardiography or dobutamine stress echocardiography [DSE]). Between December 2012 and January 2013, all patients were contacted to verify the occurrence of cardiac events. Patients were divided in 3 subgroups according to peak stress Wall Motion Score Index (pWMSI): normal peak wall motion (pWMSI, 1; group A1), mild to moderate peak asynergy (pWMSI, 1.1-1.7; group A2), and severe peak asynergy (pWMSI, N 1.7; group A3). Results: Stress echocardiography showed inducible ischemia in 159 patients (25%); it was negative in 425 (68%) and inconclusive in 42 (7%). Patients with cardiac events more frequently showed inducible ischemia (50% vs 26%; P =

.015) compared with patients with good prognosis; a normal SE (14% vs 61%) was significantly less common. At a multivariate regression analysis, an increased pWMSI (relative risk: 9.816, 95% confidence interval: 3.665-26.290; P b

.0001) was independently associated with a bad outcome. Cumulative event-free survival was significantly worse with an increasing degree of peak wall motion asynergy (99% in group A1; 96%, group A2; and 88% in group A3; P =

.011 between A1 and A2 groups, P = .012 between A2 and A3 groups, and P b .0001 between A1 and A3 groups). Conclusions: Stress echocardiography showed an optimal prognostic value among ED patients evaluated for chest pain. The presence of an extensive asynergic area at peak stress was associated with an adverse prognosis.

(C) 2014

Introduction

Chest pain or other symptoms consistent with myocardial ischemia are the second most frequent cause of ED presentation in adults in the United States; however, less than 5% of these patients have an ST-segment elevation myocardial infarction [1], whereas an increasing proportion of patients are affected by a Non-ST-segment elevation myocardial infarction [2]. Thus, although an aggressive treatment is needed for patients with acute coronary syndrome (ACS), an accurate diagnostic assessment is required for patients with less critical syndromes, avoiding hazardous or unnecessary evaluations. Exercise electrocardiogram (ECG) is the first choice test in patients with normal baseline ECG and presumed normal exercise capacity; by using exercise ST depression to define a positive test, the reported exercise ECG sensitivity and specificity for coronary disease diagnosis range between 23% and 100% (mean, 68%) and 17 and 100% (mean, 77%), respectively [3]. Considering the specific ED setting, several articles demonstrated that stress echocardiography (SE) was more effective than exercise ECG in terms of diagnostic accuracy and risk

* Corresponding author: Lg. Brambilla 3, 50134 Firenze, Italy. Tel.: +39 055 7947748.

E-mail address: [email protected] (F. Innocenti).

stratification [4]. Stress echocardiography results are commonly expressed as positive or negative for inducible ischemia; nonetheless, SE may yield adjunctive and valuable information, like global left ventricular (LV) systolic function at rest and extension and severity of baseline and peak asynergic area [5,6]. In the Scientific Statement of the American Heart Association, the authors underline that the primary goal of these patients’ evaluation in ED is an accurate risk stratification by the exclusion of ACS and other Serious condition rather than the detection of coronary artery disease (CAD) [1]. To obtain an accurate risk stratification of patients with chest pain, it could be useful to take into account all the information given by an SE, keeping in mind their prognostic value.

Aims of this study were (1) to evaluate the long-term prognostic value of SE performed in patients presenting to the ED with spontaneous chest pain and (2) to determine SE parameters that best predict outcome.

Methods

Study population

In our hospital, all patients who present to the ED with spontaneous chest pain, nondiagnostic ECG, and negative cardiac necrosis markers are managed in the observation unit (OU); in the

http://dx.doi.org/10.1016/j.ajem.2014.03.026

0735-6757/(C) 2014

exercise stress test protocol”>follow-up data“>OU, they perform the second and third evaluations of the necrosis markers (after 6 and 12 hours from ED admission) as well as the stress test. We retrospectively identified all consecutive unselected patients who were evaluated in the OU with SE between June 2008 and July 2012 for CAD screening; no exclusion criteria was applied. Among patients evaluated with SE, the first choice provocative test was exercise stress echocardiography (ESE); nevertheless, dobutamine stress echocardiography (DSE) was used as stressor in presence of reported exercise deconditioning, coexisting disease precluding the performance of maximal effort, and permanent left bundles branch block (LBBB) on the ECG. At the moment of the test, main clinical data were collected, especially regarding pain characteristics, cardiovas- cular risk factors, and previous cardiovascular disease.

Chest pain characteristics were encoded according to a modified Chest Pain Score [7,8], which takes into account the following: pain characteristics (crushing; pressing; heaviness, 3; sticking; pleuritic; and pinprick, 1), localization (substernal or precordial, 3; epigastric; left chest; neck; and lower jaw, 1), radiation (as either arm; shoulder; back; neck; lower jaw, 1; and absence, 0), associated symptoms (as dyspnea; nausea; diaphoresis, 2; and absence, 0), and recurrence in the previous 7 days (yes, 3; and no, 0).

All patients gave their informed consent, and the study is consistent with the principles of the Declaration of Helsinki of clinical research involving human patients.

Exercise stress test protocol

The exercise stress test (EST) was performed according to the standard Bruce protocol, aiming at reaching at least the 85% of the age-adjusted maximal predicted heart rate (MPHR) (percent MPHR, [220, age in years] x 0.85); the test was considered positive if at least 1 mm ST-segment depression measured at 80 milliseconds after J point developed at peak stress or during recovery. Before and immediately after exercise completion, echocardiographic images (iE33; Philips Medical System, Andover, MA) in the parasternal long- and short-axis and apical 4- and 2- chamber view were acquired to allow quad- screen visualization. With evidence of new or worsening wall motion abnormalities at poststress examination, the test was considered positive, regardless the presence of symptoms or ECG changes.

The EST was considered inconclusive for inability to reach 85% MPHR, in absence of ECG and echocardiographic changes. The test was prematurely terminated in the presence of angina, ischemic ST-segment depression more than 2 mm, significant ventricular ectopy, systolic blood pressure (SBP) more than 250 mm Hg, or excessive blood pressure decrease during exercise. The test was considered normal if 85% of MPHR was reached without symptoms, ECG, and echocardiographic abnormalities. Peak exercise capacity from the treadmill test was estimated in Metabolic equivalents (METs), using data from standard predicted equations.

Dobutamine stress protocols

?-blocker therapy was not administered the day of the test. After baseline echocardiogram, the patients underwent DSE according to standard protocol [9]. Test end points were achievement of target heart rate, positive ischemic response indicated by development of new asynergia in 2 or more myocardial segments, excessively increased (SBP, N 240 mm Hg) or reduced (drop, N 40 mm Hg from precedent phase or SBP, b 90 mm Hg) blood pressure, repetitive ventricular or supraven- tricular ectopy, or ischemic ECG changes. If the test was positive for ischemia, metoprolol was infused in incremental doses of 0.5 mg, until ECG and echocardiographic modifications resolved.

Echocardiographic analysis

Left ventricular end-diastolic and end-systolic volumes were calculated by Simpson rule; all values were indexed by body surface

area. At baseline, at peak stress and after recovery, digitized images, from parasternal long- and short-axis and apical 4- and 2-chamber views were stored on disk, to allow quad-screen visualization. Left ventricular regional wall motion was assessed according to the recommendations of the American Society of Echocardiography, based on a 16-segment model in which each segment was scored 0, not visualized; 1, normokinetic; 2, hypokinetic; 3, akinetic; 4, dyskinetic; or 5, aneurysm. Wall Motion Score Index (WMSI) was calculated at baseline and peak stress as the ratio between the cumulative sum score and the number of visualized segments. Inducible ischemia was defined as the development, in at least 2 adjacent segments of new asynergia or biphasic response (basal asynergia improving at low dose and worsening at high dose dobutamine infusion). For further analysis, patients were divided in

3 subgroups according to peak stress Wall Motion Score Index (pWMSI): normal peak wall motion (pWMSI, 1; group A1), mild to moderate peak asynergy (pWMSI, 1.1-1.7; group A2), and severe peak asynergy (pWMSI, N 1.7; group A3). A normal SE was defined as normal wall motion at rest, with increase in wall thickening and excursion during stress.

Follow-up data

Data about coronary angiographies performed by patients with positive SE were collected from medical records, to verify the presence of Significant coronary lesions. Significant coronary disease was defined as more than 50% luminal diameter stenoses in any of the major coronary branches. Between December 2012 and January 2013, all patients were contacted to verify the occurrence of new major events (cardiac death, nonfatal ACS, ACS, and revascularization procedures) by means of a physician-directed telephone interview using a standardized questionnaire. All hospital medical records of patients who reported new cardiac events were reviewed, to confirm data reported by patients during the phone call.

Statistical analysis

Data were analyzed with SPSS program (SPSS Inc, Chicago, IL). Parametric data were reported as mean +- SD. The comparison between 2 groups was made with Student t test for noncoupled parametric data. Nonparametric data were analyzed with Fisher exact test. Variables identified as potential prognostic predictors for multivariate modeling were selected by backward method (likelihood ratio method, with variable in by P b .05 and out, P N .10 to avoid biases due to colinearity). survival analysis was performed by Kaplan-Meier method. A P b .05 was considered significant.

Results

Between June 2008 and July 2012, 777 patients underwent SE for CAD screening; in December 2012, all patients were contacted by phone to verify the occurrence of new cardiac events. Six hundred twenty-six subjects answered the phone call, and they represented our study population. Participants showed a similar age (67 +- 13 vs 67 +- 14 years), left ventricular ejection fraction (LV EF) (60 +- 12% vs 57 +- 12%), prevalence of history of known CAD (26% vs 28%), and inducible ischemia during SE (27% vs 29%; all P = not significant [NS]) than nonparticipants (n = 151).

Clinical, rest, and SE characteristics are shown in Table 1. Stress echocardiography showed inducible ischemia in 159 patients (25%), it was negative in 425 (68%), and inconclusive in 42 (7%). Patients lost to follow-up demonstrated a similar prevalence of test results, respec- tively 26%, 65%, and 9% (all P = NS). One hundred twelve patients with inducible ischemia underwent a coronary angiography that demonstrated a critical coronary stenoses in 87 patients. A percuta- neous coronary revascularization was performed in 34 patients. Stress

echocardiography was normal in 352 patients and abnormal in 253; 21 patients with normal wall motion at rest and inconclusive SE were excluded from this analysis.

Predictors of all-cause mortality

Patients were followed up for up to 4.5 years (mean, 854 +- 416 days), and 100% were followed for 6 months. During the follow-up period, 23 patients died, 9 for cardiovascular disease (6 patients for ACS, 2 for stroke, and one for an abdominal aortic aneurism). Clinical and echocardiographic characteristics according to all-cause mortality are shown in Table 1. Compared with survivors, nonsurvivors showed more frequently inducible ischemia and, accordingly, critical coronary stenoses at coronary angiography (36% vs 12%; P = .001); a percutaneous revascularization procedure was performed in a comparable proportion of patients (14% vs 5%; P = NS). Rest wall motion abnormalities were more frequent among patients with a bad prognosis (61% vs 29%; P = .001) than among survivors, whereas a normal SE was an exception.

We performed a multivariate logistic regression analysis that included all significantly different parameters according to all-cause mortality (age, diabetes, peripheral arterial disease, rest and pWMSI, stressor, normal SE, presence of inducible ischemia, and critical coronary lesions); an advanced age (odds ratio, 1.147/year; 95% confidence interval [CI], 1.072-1.228; P b .0001) and the presence of peripheral arterial disease (relative risk [RR], 2.993; 95% CI, 1.034- 8.665; P = .043) were independent predictors of an adverse prognosis, whereas a normal SE (RR, 0.062; 95% CI, 0.008-0.473; P = .007) was associated with a good outcome. We repeated the analysis after excluding age, given the correlation between an advanced age and an increased all-cause mortality: a pharmacologic stress (RR, 4.040; 95% CI, 1.297-12.587; P = .016) and presence of peripheral

arterial disease (RR, 3.103; 95% CI, 1.127-8.547; P = .028) were

Table 1

Clinical and echocardiographic characteristics in the whole study population and according to all-cause mortality

associated with increased mortality; again, a normal SE (RR, 0.050; 95% CI, 0.007-0.382; P = .004) was an independent predictor of a good prognosis.

SE and follow-up cardiac events

We excluded from this analysis patients who died of noncardiac disease (n = 14). During follow-up, 21 cardiac events occurred: 13 nonfatal ACS, 6 fatal ACS, and 2 ventricular tachycardia.

Clinical and echocardiographic characteristics according to event- free survival are shown in Table 2. Patients with cardiac events on follow-up were older and showed a higher prevalence of peripheral arterial disease and history of known CAD than patients with a good prognosis; they also showed higher LV volumes and a significantly worst global and segmental systolic function. They were less likely to undergo an ESE, and they more frequently showed inducible ischemia compared with patients with good prognosis; a normal SE was significantly less common. Presence of critical coronary stenoses (33% vs 12%; P = .005) and, consequently, percutaneous revascularization procedures (29% vs 5%; P b .0001) were significantly more common among patients with unfavorable outcome compared with patients with good prognosis. Cardiac event rate was 2.4% (10/421) among patients with negative SE for inducible ischemia and 6.7% (10/151; P = .020) among patients with inducible ischemia; one event occurred in a patient with an inconclusive test. Patients with normal SE showed a cumulative cardiac event rate of 0.9% (3/351), compared with 8% among patients with an abnormal SE (18/241; P b .0001). A Kaplan-Meier analysis evidenced a significant better event-free survival for patients with a normal SE (99% vs 93%; P b .0001) (Fig. 1) compared with patients with an abnormal test; patients with a negative SE for inducible ischemia showed a better prognosis (98% vs 93%; P = .028) compared with patients with positive SE.

We performed a multivariate logistic regression analysis that included

all significantly different parameters between patients with good or bad prognosis (presence of peripheral arterial disease, history of CAD, inducible ischemia, normal SE, critical coronary lesions, and baseline

All

(N = 626)

Survivors (n = 603)

Nonsurvivors P

(n = 23)

Table 2

Clinical and echocardiographic characteristics according to event-free survival

Age (y)

67 +- 12

66 +- 12

79 +- 8

b.0001

Male, sex (%)

361 (58%)

349 (58%)

12 (52%)

.587

No events Cardiac events P

Hypertension (%)

389 (62%)

372 (62%)

17 (74%)

.243

(n = 591)

(n = 21)

Diabetes (%)

104 (17%)

96 (16%)

8 (35%)

.018

Age (y)

66 +- 12

74 +- 10

.006

Arterial disease (%)

65 (11%)

57 (10%)

8 (35%)

b.0001

Male, sex (%)

340 (58%)

14 (67%)

.405

Known CAD

162 (26%)

154 (26%)

8 (35%)

.344

Arterial hypertension (%)

364 (62%)

16 (76%)

.178

Chest Pain Score

5.9 +- 3.1

5.8 +- 3

6.8 +- 3

.169

Diabetes (%)

95 (16%)

3 (14%)

.920

Medications

Peripheral arterial disease (%)

53 (9%)

6 (30%)

.002

acetylsalicylic acid (ASA) (%)

232 (38%)

220 (38%)

12 (52%)

.158

Known CAD

145 (25%)

13 (62%)

b.0001

? blockers (%)

159 (26%)

153 (26%)

6 (26%)

.994

Chest Pain Score

5.8 +- 3.1

6.6 +- 3.1

.169

ACE inhibitors (%)

183 (30%)

172 (30%)

11 (48%)

.060

Medications

Calcium antagonists (%)

90 (15%)

86 (15%)

4 (18%)

.722

ASA (%)

211 (37%)

12 (57%)

.058

Nitrates (%)

40 (7%)

36 (6%)

4 (17%)

.033

ACE inhibitors (%)

166 (29%)

12 (57%)

.006

Statins (%)

183 (30%)

176 (30%)

7 (30%)

.971

? blockers (%)

146 (25%)

9 (43%)

.074

Rest echocardiography

Calcium antagonists (%)

82 (14%)

5 (24%)

.225

LVEDVi (mL/m2)

51 +- 16

50 +- 16

56 +- 19

.219

Nitrates (%)

34 (6%)

4 (19%)

.016

LVESVi (mL/m2)

22 +- 12

21 +- 12

29 +- 18

.122

Statins (%)

167 (29%)

10 (48%)

.068

LVMI (g/m2)

85 +- 25

84 +- 24

99 +- 43

.027

Rest echocardiography

LV EF (%)

59 +- 12

60 +- 12

51 +- 15

.048

LVEDVi (mL/m2)

50 +- 16

64 +- 21

.017

SE

LVESVi (mL/m2)

21 +- 12

35 +- 19

.012

Baseline WMSI

1.21 +- 0.41

1.20 +- 0.40

1.52 +- 0.53

.009

LVMI (g/m2)

84 +- 25

99 +- 26

.038

pWMSI

1.29 +- 0.44

1.27 +- 0.44

1.70 +- 0.48

b.0001

LV EF (%)

60 +- 12

48 +- 16

.010

METS at peak stress

6.3 +- 1.5

6.4 +- 1.5

5.0 +- 0.1

b.0001

SE

Exercise/dobutamine

365/261

360/243

4/19

b.0001

Baseline WMSI

1.19 +- 0.38

1.75 +- 0.71

.002

Inducible ischemia (%)

159 (27%)

144 (26%)

15 (71%)

b.0001

pWMSI

1.26 +- 0.42

1.92 +- 0.60

b.0001

Normal SE

352 (58%)

350 (60%)

2 (0.6%)

b.0001

METS at peak stress

6.4 +- 1.5

5.8 +- 1.3

.317

Abbreviations: ACE, angiotensin-converting enzyme; LVEDVi, left ventricular end- diastolic volume index; LVESVi, left ventricular end-systolic volume index; LVMI, left ventricular mass index.

Exercise/dobutamine

356/235

6/15

.004

Inducible ischemia (%)

141 (26%)

10 (50%)

.015

Normal SE

349 (61%)

3 (14%)

b.0001

and pWMSI); only an increased pWMSI (RR, 9.816, 95%CI, 3.665-26.290;

P b .0001) was independently associated with a bad outcome.

Clinical characteristics and outcome according to stressor

Three hundred sixty-five patients underwent ESE, and 261 underwent DSE. Clinical and echocardiographic characteristics ac- cording to the used stressor are shown in Table 3. Patients who underwent DSE showed a higher prevalence of inducible ischemia and critical coronary lesions (18% vs 10%; P = .005) compared with patients evaluated with ESE; a similar proportion of patients (6%) underwent a percutaneous coronary angioplasty. A nonconclusive test occurred in a similar proportion of patients.

A cardiac event occurred in 6 (1.7%) of 362 patients who underwent ESE, all with a history of CAD; patients evaluated with

Table 3

Clinical and echocardiographic characteristics according to stressor

ESE (n = 365) DSE (n = 261) P

Age (y) 61 +- 12 74 +- 10 b.0001

Male, sex (%) 246 (67%) 115 (44%) b.0001

Arterial hypertension (%) 201 (55%) 188 (73%) b.0001

Diabetes (%) 38 (10%) 66 (26%) b.0001

Peripheral arterial disease (%) 27 (8%) 38 (15%) .003

Known CAD 85 (23%) 77 (30%) .055

Rest echocardiography

LVEDVi (mL/m2)

50 +- 14

52 +- 19

NS

LVESVi (mL/m2)

20 +- 9

25 +- 17

.001

LV EF (%)

61 +- 10

55 +- 14

b.0001

SE

Baseline WMSI

1.15 +- 0.34

1.30 +- 0.48

b.0001

pWMSI

1.21 +- 0.38

1.40 +- 0.50

b.0001

Categorized pWMSI

b.0001

Normal pWMSI (%)

257 (70%)

130 (50%)

DSE reported 14 cardiac event (14/250, 6%; P = .01 vs ESE), 6 in

Moderate pWMSI abn (%)

58 (16%)

68 (26%)

patients with CAD, and 8 in patients without known CAD (Fig. 2). Time

Severe pWMSI abnes (%)

50 (14%)

63 (24%)

interval between SE and the cardiac event was significantly higher in patients with a negative SE compared with those with a positive test (726 +- 503 vs 322 +- 324 days; P = .047). It is noteworthy that, among 58 patients with a positive ESE for inducible ischemia, 24 did not develop symptoms or ECG modifications suggestive for inducible ischemia; therefore, they would be considered as negative tests according to exercise ECG results.

pWMSI and cardiac event rate

Cardiac event rate increased as a function of peak extent of wall motion abnormalities: group A1 patients reported 3 cardiac events (0.8%); group A2 patients, 5 events (4%); and group A3 patients, 13 events (13%; P b .0001). Patients with normal pWMSI who reported a cardiac event did not have a history of known CAD, but all underwent DSE. A Kaplan-Meier analysis showed that cumulative event-free survival was significantly worse with an increasing degree of peak wall motion asynergy (99% in group A1; 96%, group A2; and 88% in group A3; P = .011 between A1 and A2 groups, P = .012 between A2 and A3 groups, and P b .0001 between A1 and A3 groups) (Fig. 3). This result was confirmed examining separately patients who underwent ESE (cumulative event-free survival respectively 100% in A1, 97% in A2, and 92% in A3 patients; P = .003 between A1 and A2 groups, P =

.218 between A2 and A3 groups, and P b .0001 between A1 and A3 groups) and patients who underwent DSE (cumulative event-free survival respectively 98% in A1, 95% in A2, and 84% in A3 patients; P =

.341 between A1 and A2 groups, P = .030 between A2 and A3 groups, and P b .0001 between A1 and A3 groups). The observed lack of

Normal SE Abnormal SE

100

P < .0001

95

90

85

80

0 500 1000 1500 2000

(Days)

Fig. 1. Event-free survival of patients (n = 612) according to presence of a normal or abnormal SE.

Rest WMA (%)

87 (24%)

102 (39%)

b.0001

Nonconclusive test

25 (7%)

29 (11%)

NS

Inducible ischemia (%)

59 (17%)

100 (43%)

b.0001

Normal SE (%)

242 (68%)

110 (44%)

b.0001

Abbreviations: CAD coronary artery disease; LVEDVi left ventricualr end-diastolic volume index; LVESVi left ventricular end-systolic volume index; LV EF left ventricular ejection fraction; SE stress-echo; pWMSI peak Wall Motion Score Index; ABN abnormalities; WMA Wall Motion Abnormalities.

significance for the intermediate group could be due to the overall small number of events observed in each subgroup.

Discussion

This study confirmed the optimal long-term SE prognostic value among ED patients who presented for spontaneous chest pain. A negative ESE in patients without a history of CAD carried an excellent prognosis; after DSE, prognosis was less favorable, regardless the presence of a known CAD. Beyond a dichotomic interpretation of SE results as positive or negative, the presence of an extensive asynergic area at peak stress was associated with an adverse prognosis.

Use of SE for CAD screening in ED has been extensively evaluated, and diagnostic accuracy was proven to be very good. Stress echocardiography was superior to exercise electrocardiogram in risk stratification of patients with suspected CAD and demonstrated a significant Cost benefit because it resulted in less diagnostic uncertainty and fewer referral for further investigations [10]. In a group of patients with discordant exercise ECG and SE, Langdorf et al

[11] demonstrated that the addition of SE altered diagnosis and changed management in up to half the study population. A positive DSE for inducible ischemia demonstrated an independent prognostic value for new cardiac events during a 6-month follow-up [12].

This is the first article to evaluate SE long-term prognostic value among patients evaluated in the ED. In this large population followed up for up to 4.5 years, presence of inducible ischemia was associated with a reduced event-free survival. On the other side, a normal SE was associated with a reduced all-cause mortality and a very good event- free survival. The high negative predictive value of a negative ESE was evidenced in a meta-analysis by Metz et al [13] and was confirmed in ED patients. In a very large population of patients with a negative exercise ECG, echocardiography showed the presence of inducible ischemia in a relevant proportion of patients; presence of worsening wall motion abnormalities during the test yielded an independent prognostic value for all-cause mortality and new cardiac events [14]. On the other side, in a long-term follow-up of a large population after a normal DSE, prognosis was not necessarily benign: age, diabetes, and failure to achieve percent MPHR were independent predictors of all-cause mortality and cardiac events [15]. We confirmed that, in absence of a known CAD, patients with a negative ESE did not report

612 patients evaluated with SE

362 patients evaluated with ESE

250 patients evaluated with DSE

13 (4%) non conclusive ESE

27 (11%) non conclusive DSE

268 (74%)

patients without history of CAD

81 (22%) patients with

known CAD

156 (62%)

patients without history of CAD

67 (27%) patients with

known CAD

4 Events

4 Events

34 (14%) SE+

33 (13%) SE-

5 Events

3 Events

60 (24%) SE+

96 (38%) SE-

3 Events

3 Events

23 (6%) SE+

58 (16%) SE-

No event

No event

34 (9%) SE+

234 (64%) SE-

Fig. 2. flow charts of patients: incidence of new cardiac events according to history of CAD and SE results.

any new cardiac event and thus represented a true low-risk subgroup for which no further testing was needed.

Compared with an exercise ECG, ESE implies a limited additional work: every patient, who undergoes an exercise ECG, needs a baseline Echocardiographic examination, to exclude significant cardiac or valvular abnormalities. An ESE requires an adjunctive echocardio- graphic evaluation at peak stress: this limited task translates into a significant gain in diagnostic accuracy and prognostic stratification. As reported by the American Heart Association [1], the inadvertent discharge of a patient with an ACS from the ED actually occurs in more than 2% of patients presenting with spontaneous chest pain. In these patients, the risk-adjusted mortality ratio is nearly 2-fold compared with patients hospitalized for ACS and is also associated with a relevant physician’s liability. Ultrasound represents an imaging modality that does not carry any biological risk for patients and implies low costs and low time burden; their addiction to Standard ECG stress test could help in reducing ACS missed diagnosis.

Normal p WMSI Mildly abn. pWMSI

Severely abn. p WMSI

100

P < .0001

Event-free survival (%)

90

80

70

60

0 300 600 900 1200 1500 1800

Days

Fig. 3. Event-free survival across pWMSI categories.

Peak asynergy extension and severity reflects both the consequence of previous Ischemic events and the presence of inducible ischemia; it represents a powerful predictor of new cardiac events, whatever the used stressor. In the perspective of an emergency physician, a negative test for inducible ischemia allows an early discharge; SE portends a very good diagnostic accuracy [16], making the emergency physician safe in this option. Nonetheless, presence of a severe peak SE asynergy that could be due to previous ischemic events identifies high-risk patients; it could be very useful to make available such information for the following management of these patients.

The retrospective design of this study and the single-center design represent significant limitations. The number of patients lost to follow-up was not negligible; however, we did not have evidence of significant differences when compared with study participants. We could not know anything about the outcome of patients lost to follow- up, and therefore, we cannot exclude the occurrence of new cardiac events among them. This relevant proportion of lost patients represents a significant limitation, but it could be justified by the long duration of the follow-up.

We did not systematically evaluate SE diagnostic accuracy compared with coronary angiography; however, the aim of this study was the evaluation of SE prognostic value, regardless the presence of critical coronary stenoses.

Conclusions

We evaluated a large population of consecutive patients, evaluated in ED for spontaneous chest pain, followed up for up to 4.5 years; in this setting, SE showed an optimal prognostic value in terms of all- cause mortality and event-free survival. Beyond the presence of inducible ischemia, SE was able to give adjunctive information, like extension and severity of peak stress asynergy, which demonstrated an independent prognostic value. The need of a pharmacologic stressor identifies an at-risk population, and its use requires a high expertise. In patients who can perform a maximal exercise, addiction

of rest and peak echocardiographic evaluation to usual ECG could improve diagnostic performance and prognostic stratification.

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