Clinical Investigations Association Between Electrocardiographic Findings, Right Heart Strain, and Short-Term Adverse Clinical Events in Patients With Acute Pulmonary Embolism
Address for correspondence: Christopher Kabrhel, MD Center for Vascular Emergencies Department of Emergency Medicine Massachusetts General Hospital Zero Emerson Place, Suite 3B Boston, MA 02114 [email protected]
Praveen Hariharan, MBBS, MPH; David M. Dudzinski, MD, JD; Ikenna Okechukwu, MD; James Kimo Takayesu, MD, MS; Yuchiao Chang, PhD; Christopher Kabrhel, MD, MPH Center for Vascular Emergencies, Department of Emergency Medicine (Hariharan, Okechukwu, Takayesu, Kabrhel), Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Division of Cardiology (Dudzinski), Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Department of Medicine (Chang), Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
Background: Electrocardiographic (ECG) changes may be seen with pulmonary emboli (PE). Whether ECG is associated with short-term adverse clinical events after PE is less well established. Hypothesis: ECG findings are associated with short-term clinical deterioration after PE. Methods: Consecutive adult PE patients were enrolled in an academic emergency department from 2008 to 2011. The primary outcome was right heart strain (RHS) on echocardiogram or CT pulmonary angiography, or TnT ≥0.1 ng/mL. We derived an ECG (TwiST) score that is associated with RHS and short-term adverse clinical events. Results: We enrolled 298 patients with PE. On multivariate analysis, T-wave inversion in leads V1 through V3 (OR: 4.7, 95% confidence interval [CI]: 1.7-13.2), S wave in lead I (OR: 2.0, 95% CI: 1.1-3.5), and tachycardia (OR: 2.5, 95% CI: 1.3-4.8) were associated with RHS. A TwiST score ≤2 (n = 210, 72%) was 84% (95% CI: 77%-90%) sensitive for the absence of RHS, whereas a TwiST score ≥5 (n = 47, 16%) was 93% (95% CI: 88%-97%) specific for the presence of RHS. Conclusions: A simple ECG (TwiST) score can identify patients likely or not likely to have RHS with >80% specificity and sensitivity and may assist in identifying patients with acute PE at risk for adverse clinical events before pursuing other advanced imaging tests.
Introduction Acute pulmonary embolism (PE) is a major health problem, accounting for >250 000 hospitalizations in the United States every year.1 The clinical outcome of acute PE varies widely, from mild symptoms and no hemodynamic consequences to cardiovascular collapse and respiratory failure.2 The American Heart Association (AHA) consensus guidelines recommend risk stratification of PE patients to guide appropriate and timely management and disposition.3
This study was funded by an award from the Harvard Milton Fund. The funding agency had no influence on the design or conduct of the study and played no role in interpreting the results or drafting the manuscript. This work was presented at the American College of Cardiology Scientific Sessions, Washington, DC, 2014. The authors have no other funding, financial relationships, or conflicts of interest to disclose. Additional Supporting Information may be found in the online version of this article.
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Risk stratification of PE involves weighing various risk predictors including age, demographics, comorbidities, and physical examination findings, as well as cardiac biomarkers and advanced cardiac imaging.4 Although the electrocardiogram (ECG) is inexpensive and universally performed in patients with PE, it is seldom incorporated into risk-stratification models. It is estimated that 70% of PE patients have abnormal ECG recordings.5 Certain ECG findings with PE may suggest right heart strain (RHS) and therefore might be used to prioritize care in these high-risk patients.6 – 9 As echocardiography is not routinely available during all hours of the day in many medical centers,10 ECG could be a useful tool for risk-stratifying PE patients. Electrocardiographic findings have been shown to correlate with the right ventricular (RV) strain and severe pulmonary hypertension after PE.7,10 However, ECG-based scores have not been directly validated against short-term adverse clinical events occurring during a typical postPE hospitalization. We sought to determine whether ECG findings are associated with RHS and short-term adverse clinical events after PE. Received: August 13, 2014 Accepted with revision: December 4, 2014
Methods Design We performed this study at Massachusetts General Hospital, an urban university hospital with an annual emergency department (ED) volume of 95 000 patient visits. We prospectively enrolled adult (age ≥18 years) ED patients diagnosed with radiographically proven PE between October 2008 and December 2011. We conducted the study in accordance with the published Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement.11 We used 2 methods for identifying consecutive patients with PE: (1) ED research staff screened for patients in the ED for 16 hours per day (from 7 AM to 11 PM) during weekdays; and (2) every morning a list of patients who had undergone computed tomography pulmonary angiography (CTPA) and ventilation/perfusion (V/Q) scans was generated and screened to identify patients who presented to the ED within the last 24 hours. These 2 complementary methods allowed us to enroll consecutive patients on all days except Saturday. Trained research staff using a standard form collected data. The Human Research Committee of Partners Healthcare approved the study. Subject Eligibility All PE patients diagnosed within 24 hours of ED registration who could provide informed consent were deemed eligible for the study. Subjects transferred from outside facilities to the ED with PE were eligible if they were enrolled in the study within 24 hours of diagnosis. Pulmonary embolism was diagnosed by either (1) a CTPA of the chest showing a filling defect in a pulmonary artery; (2) a computed tomography (CT) venogram, performed in conjunction with a CTPA in a patient with symptoms of PE (chest pain or dyspnea), showing a filling defect in a proximal deep vein of the leg consistent with deep-vein thrombosis; (3) positive venous ultrasound of an extremity consistent with deep-vein thrombosis in a patient with symptoms of PE (chest pain or dyspnea) who was subsequently treated for presumed PE; or (4) a V/Q scan read as high-probability for PE according to the Prospective Investigation of Pulmonary Embolism Diagnostic (PIOPED) criteria.12 Board-certified radiologists interpreted all radiographic findings as part of routine clinical care. Patients were excluded if they were age 100 bpm. SIQIIITIII was defined as presence of any S wave in lead I, Q wave (>1.5 mm deep) in lead III, and any TWI in lead III. A RBBB was defined as QRS duration >120 ms with terminal R wave in lead V1 and terminal S wave in lead I and V6 . Incomplete RBBB was defined as a QRS duration 100 to 120 ms and morphology otherwise similar to RBBB. We defined ST elevations, ST depressions, and TWI as either present or absent in each lead, but we did not quantify the magnitude of these deflections. We assessed the association of these ECG findings with RHS and adverse clinical events. We also determined the association of the ECG score published by Daniel et al10 with RHS and adverse clinical events in the patients in our cohort. In brief, the score by Daniel et al is a 21-point scoring system that includes tachycardia, incomplete and complete RBBB, depth of TWI on anterior ECG leads, and SIQIIITIII pattern.10 Primary Outcome Right Heart Strain: We defined RHS based on any 1 of the following: echocardiography, CTPA, or biomarker results. Diagnostic imaging (CPTA and echocardiography) were performed at the discretion of the treating physician. All echocardiograms were performed in accordance with the recommendations of the American Society of Echocardiography within 3 days of diagnosis of PE.13 Right ventricular (RV) strain was confirmed by the presence of RV hypokinesia, dilatation, and abnormal interventricular septum movement.14 In CTPA, a right ventricle/left ventricle (RV/LV) ratio >1 was considered positive for RV strain. Assay of troponin-T (Troponin-T STAT, COBAS 6000-CE, Roche, Indianapolis, IN, USA) was considered positive at ≥0.1 ng/dL. When an echocardiogram was not performed for clinical purposes, it was considered negative for the purposes of this analysis. When echocardiogram or Tn results were positive, a subject was deemed to have RHS. When echocardiogram results were not available and Tn was negative, then RHS was considered present if the RV/LV ratio was >1 on CTPA. Secondary Outcome and Subanalysis Our secondary outcome was designed to identify patients who suffer adverse clinical events within 5 days of diagnosis of PE (see Supporting Table 1 in the online version of this article).15 This timeframe was chosen based on prior literature and is consistent with a typical length of hospitalization for PE.16 Statistical Analysis Baseline data were reported as mean ± SD for continuous variables and as simple proportions for categorical variables. Univariate and sensitivity analysis were performed using ECG findings for our primary outcome of RHS. The association between ECG findings and RHS was summarized using test characteristics (sensitivity, specificity, odds ratios [ORs]) and examined using χ2 tests. Subsequently, Clin. Cardiol. 38, 4, 236–242 (2015) P. Hariharan et al: Right heart strain after acute PE Published online in Wiley Online Library (wileyonlinelibrary.com) DOI:10.1002/clc.22383 © 2015 Wiley Periodicals, Inc.
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we performed a multivariate analysis using the ECG findings revealing highest association from the univariate analysis and formulated a new ECG score. We used the new ECG score to obtain test characteristics at different cutoffs, and for our primary and secondary outcome in all patients. We performed a similar analysis with the ECG score by Daniel et al.10 Because the presence of chronic cor pulmonale and coronary artery disease (CAD) can be associated with ECG changes similar to those seen in acute PE, we performed a subanalysis of the ECG score excluding patients with a prior history of chronic lung disease and CAD. We also performed a subanalysis reclassifying patients (n = 23) who had RHS on CT but negative echocardiograms as not having RHS. The SAS software version 9.3 (SAS Institute Inc., Cary, NC) was used for all analyses.
Table 1. Characteristics of Enrolled Patients Characteristic Mean age, y
59 ± 17
Male sex
147 (51)
Race White
261 (90)
Black
17 (6)
Asian
3 (1)
Other
9 (3)
Ethnicity Non-Hispanic
Results We identified 403 consecutive patients with PE, and enrolled 301. The most common reasons patients were not enrolled were presentation on Saturday (n = 39), patient declined enrollment (n = 28), and inability to understand consent (n = 17) due to language or altered mental status. An ED ECG was available for review in 290 (97%) subjects, and these patients were included in our analysis. Radiologic and biomarker testing included CTPA (280/290, 97%), V/Q (4/290, 1%), lower-extremity ultrasound (94/290, 32%), CT venography (132/290, 46%), echocardiography (117/290, 40%), and Tn (290/290, 100%). Table 1 describes baseline characteristics of patients included in the analysis. Mean age was 59 ± 17 years; 51% were male and 90% described themselves as white. Notably, 36% (105 patients) had a history of malignancy. One hundred forty-six (50%) patients had RHS. Among patients with RHS, 51 (35%) were identified based on echocardiographic findings, 127 (87%) based on CTPA, and 12 (8%) based on a positive Tn. A positive Tn was noted in 1 subject with renal insufficiency (n = 8), 2 subjects with history of CAD (n = 26), and 1 subject history of congestive heart failure (n = 12). None of the enrolled subjects had concomitant acute coronary syndrome or acute congestive heart failure. Table 2 describes the univariate analysis of ECG characteristics for RHS. An S wave in lead I was the most common finding (81, 28%), followed by TWI in lead III (79, 27%) and HR >100 (58, 20%). An S wave in lead I, TWI in lead V1 through V2 , TWI in lead V1 through V3 , tachycardia, and incomplete RBBB were significantly associated with RHS. The classic SIQIIITIII finding was uncommon (15, 5%). Table 3 describes the results from the multivariable logistic regression model. Electrocardiographic patterns independently associated with the primary outcome were TWI in lead V1 through V3 (OR: 4.8, 95% confidence interval [CI]: 1.7-13.2), S wave in lead I (OR: 2.0, 95% CI: 1.1-3.5), and tachycardia (OR: 2.6, 95% CI: 1.4-4.8). Based on these results, we created a simple 10-point ECG score, the TwiST score, which includes TWI in leads V1 through V3 (5 points), S wave in lead I (2 points), and tachycardia (3 points). Table 4 shows the test characteristics of the TwiST ECG score for our primary outcome of RHS. In our cohort, 210 (72%) patients had a TwiST score ≤2 points, whereas 47
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Clin. Cardiol. 38, 4, 236–242 (2015) P. Hariharan et al: Right heart strain after acute PE Published online in Wiley Online Library (wileyonlinelibrary.com) DOI:10.1002/clc.22383 © 2015 Wiley Periodicals, Inc.
N (%) or ± SD
Hispanic
282 (97) 8 (3)
Comorbid Illness Asthma
25 (9)
COPD
14 (5)
CAD
26 (9)
CHF
12 (4)
Malignancy
105 (36)
Renal insufficiency/failure
8 (3)
Stroke or TIA
16 (6)
Prior VTE
59 (20)
Recent immobilization
70 (24)
Recent high-risk surgery
78 (27)
Abbreviations: CAD, coronary artery disease; CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; SD, standard deviation; TIA, transient ischemic attack; VTE, venous thromboembolism.
(16%) had a score ≥5 points. A TwiST score ≤2 points was 84% (95% CI: 77%-90%) sensitive for absence of RHS. A TwiST score ≥5 points was 93% (95% CI: 88%-97%) specific for RHS. When the TwiST ECG score was assessed against the rate of 5-day adverse clinical events (Table 4), the TwiST score ≤2 points was 76% (95% CI: 70%-81%) sensitive for absence of adverse clinical events, and a TwiST score ≥5 points, 87% (95% CI: 83%-91%) specific for adverse clinical events. Removing patients with a history of chronic lung disease and CAD did not change our results (data not shown). In our subanalysis reclassifying patients who had RHS on CT but negative echocardiograms as RHS negative, a TwiST score ≤2 points was 81% (95% CI: 74%-87%) sensitive for absence of RHS. A TwiST score ≥5 points was 91% (95% CI: 86%-95%) specific for RHS. Twenty-seven (9%) patients had severe outcome within 5 days of diagnosis of PE. Similarly in our cohort, 156 (54%) subjects had a Daniel et al ECG score ≤2 points as compared with 45 (16%) subjects ≥7 points. Table 5 shows the test characteristics of the Daniel et al score for our primary outcome of RHS. The Daniel et al ECG score ≤2 points was 62% (95% CI: 53%-70%)
Table 3. Multivariable Analysis of ECG Characteristics (TwiST Score) Table 2. Univariate Analysis of ECG Characteristics ECG Characteristics, N = 298
n (%)
OR (95% CI)
TWI in leads V1 through V2 a
41 (14)
2.11 (1.05-4.21)
TWI in leads V1 through V3 b
ECG Characteristics
Specificity, Sensitivity, % % 90
18
26 (9) 4.67 (1.71-12.76)
97
14
TWI in leads V1 through V4 c
12 (4) 2.03 (0.60-6.89)
97
5
S wave in lead Id
81 (28) 2.36 (1.39-4.02)
81
36
Tachycardia ≥100 bpm
58 (20) 2.64 (1.43-4.88)
88
27
Non–sinus rhythm 43 (15) 0.84 (0.44-1.60)
84
14
Q wave in lead IIIe
47 (16) 1.15 (0.61-2.14)
85
17
TWI in lead III
79 (27) 1.44 (0.86-2.43)
76
31
1.13 (0.40-3.22)
95
5
Incomplete RBBB
29 (10) 2.38 (1.05-5.42)
94
14
Complete RBBBg
13 (4)
97
6
SIQIIITIII pattern
15 (5) f
2.30 (0.69-7.64)
Abbreviations: CI, confidence interval; ECG, electrocardiogram; OR, odds ratio; RBBB, right bundle branch block; RHS, right heart strain; TWI, T-wave inversion. Sensitivity and specificity calculated for RHS. a TWI in leads V1 and V2 . b TWI in leads V1 , V2 , and V3 . c TWI in leads V1 , V2 , V3 , and V4 . d First negative deflection after R wave >1.5 mm. e First negative deflective after P waves of size >1.5 mm before any R wave. f 100 msec < QRS length < 120 msec with terminal R wave in lead V1 and terminal S wave in leads I and V6 . g QRS length > 120 msec with terminal R wave in lead V1 and terminal S wave in leads I and V6 .
TWI in leads V1 through V3
n (%) a
OR (95% CI)
P Value Points
26 (9) 4.76 (1.71-13.28)
0.003
5
S wave in lead I
81 (28) 2.04 (1.17-3.54)
0.012
2
Tachycardia ≥100 bpm
58 (20) 2.58 (1.37-4.85)
0.003
3
Abbreviations: CI, confidence interval; ECG, electrocardiogram; OR, odds ratio; TWI, T-wave inversion. Point value has been assigned to each ECG characteristic based on the parameter estimate (β) from the univariate analysis. a TWI in leads V1 , V2 , and V3 .
sensitive for absence of RHS. A Daniel et al ECG score ≥7 points was 93% (95% CI: 88%-97%) specific for RHS. When the Daniel et al ECG score was assessed for secondary outcomes (Table 5), the ECG score ≤2 points was 57% (95% CI: 50%-63%) sensitive for absence of adverse clinical events and a score ≥7 points was 87% (95% CI: 83%-91%) specific for adverse clinical events.
Discussion Electrocardiography is one of the first diagnostic tests performed for patients presenting with symptoms of PE. The AHA recommends risk stratification of acute PE patients based on RHS.3 Certain ECG characteristics have been shown to be associated with RHS but typically are not incorporated in the risk-stratification models.4,16 In this study, we found 3 ECG characteristics independently associated with RHS: TWI in leads V1 through V3 , S wave in lead I, and sinus tachycardia. We derived a simple, easyto-use, 10-point ECG score that can effectively risk-stratify 85% of acute PE patients. A TwiST ECG score ≤2 points can exclude RHS with 85% sensitivity, whereas a score of ≥5 points is 93% specific for RHS in patients with PE. The
Table 4. Test Characteristics of TwiST ECG Score at Different Cutoffs for RHS ECG Score Cutoff Points
n (%)
Sensitivity, % (95% CI)
Specificity, % (95% CI)
PPV, % (95% CI)
NPV, % (95% CI)
≤2 points
210 (72)
84 (77–90)
39 (31–47)
58 (51–64)
71 (60–81)
≥3 points
80 (28)
39 (31–47)
84 (77–90)
71 (60–81)
58 (51–64)
≥5 points
47 (16)
25 (19–33)
93 (88–97)
79 (64–89)
55 (49–62)
≥7 points
12 (4)
8 (4–14)
100 (97–100)
100 (74–100)
52 (46–58)
≥8 points
4 (1)
3 (1–7)
100 (97–100)
100 (40–100)
50 (44–56)
Score at cutoffs for RHS
Score at cutoffs for clinical deterioration ≤2 points
210 (72)
76 (70–81)
59 (39–78)
95 (91–97)
20 (12–30)
≥3 points
80 (28)
59 (39–78)
76 (70–81)
20 (12–30)
95 (91–97)
≥5 points
47 (16)
52 (32–71)
87 (83–91)
30 (17–45)
95 (91–97)
≥7 points
12 (4)
11 (2–29)
97 (94–98)
25 (5–57)
91 (87–94)
≥8 points
4 (1)
4 (0–19)
99 (97–100)
25 (1–81)
91 (87–94)
Abbreviations: CI, confidence interval; ECG, electrocardiogram; NPV, negative predictive value; OR, odds ratio; PPV, positive predictive value; RHS, right heart strain. Clin. Cardiol. 38, 4, 236–242 (2015) P. Hariharan et al: Right heart strain after acute PE Published online in Wiley Online Library (wileyonlinelibrary.com) DOI:10.1002/clc.22383 © 2015 Wiley Periodicals, Inc.
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Table 5. Test Characteristics of Daniel et al ECG Score at Different Cutoffs for RHS ECG Score Cutoff Points
n (%)
Sensitivity, % (95% CI)
Specificity, % (95% CI)
PPV, % (95% CI)
NPV, % (95% CI)
≤2 points
156 (54)
62 (53–70)
54 (46–62)
57 (49–65)
59 (50–67)
≥3 points
134 (46)
54 (46–62)
62 (53–70)
59 (50–67)
57 (49–65)
≥4 points
99 (34)
41 (33–50)
73 (65–80)
61 (50–70)
55 (48–62)
≥5 points
79 (27)
34 (26–42)
79 (72–85)
62 (50–73)
54 (47–61)
≥6 points
58 (20)
27 (20–35)
88 (81–92)
69 (55–80)
54 (48–61)
≥7 points
45 (16)
24 (17–32)
93 (88–97)
78 (63–89)
55 (48–61)
≥8 points
39 (13)
21 (15–29)
94 (89–98)
79 (64–91)
54 (48–60)
≥9 points
31 (11)
16 (11–23)
95 (90–98)
77 (59–90)
53 (47–59)
≥10 points
20 (7)
10 (6–16)
97 (92–99)
75 (51–91)
51 (45–58)
≥11 points
18 (6)
9 (5–15)
97 (92–99)
72 (47–90)
51 (45–57)
≥12 points
15 (5)
7 (3–12)
97 (92–99)
67 (38–88)
51 (44–57)
≥13 points
12 (4)
5 (2–10)
97 (92–99)
58 (28–85)
50 (44–56)
≥14 points
5 (2)
3 (1–7)
99 (96–100)
80 (28–99)
50 (44–56)
≥18 points
3 (1)
2 (0–6)
100 (97–100)
100 (29–100)
50 (44–56)
Score at cutoffs for RHS
Score at cutoffs for severe clinical outcomes ≤2 points
156 (54)
57 (50–63)
74 (54–89)
96 (91–98)
15 (9–22)
≥3 points
134 (46)
74 (54–89)
57 (50–63)
15 (9–22)
96 (91–98)
≥4 points
99 (34)
56 (35–75)
68 (62–74)
15 (9–24)
94 (89–97)
≥5 points
79 (30)
48 (29–68)
75 (69–80)
16 (9–26)
93 (89–96)
≥6 points
58 (20)
44 (25–65)
83 (77–87)
21 (11–33)
94 (90–96)
≥7 points
45 (16)
44 (25–65)
87 (83–91)
27 (15–42)
94 (90–97)
≥8 points
39 (13)
37 (19–58)
89 (85–92)
26 (13–42)
93 (89–96)
≥9 points
31 (11)
33 (17–54)
92 (88–95)
29 (14–48)
93 (89–96)
≥10 points
20 (7)
15 (4–34)
94 (90–96)
20 (6–44)
91 (87–95)
≥11 points
18 (6)
15 (4–34)
95 (91–97)
22 (6–48)
92 (88–95)
≥12 points
15 (5)
11 (2–29)
95 (92–98)
20 (4–48)
91 (87–94)
≥13 points
12 (4)
7 (1–24)
96 (93–98)
17 (2–48)
91 (87–94)
≥14 points
5 (2)
4 (0–19)
98 (96–100)
20 (1–72)
91 (87–94)
≥18 points
3 (1)
4 (0–19)
99 (97–100)
33 (1–91)
91 (87–94)
Abbreviations: CI, confidence interval; ECG, electrocardiogram; NPV, negative predictive value; OR, odds ratio; PPV, positive predictive value; RHS, right heart strain.
optimal use of the TwiST score in clinical practice may be to alert the clinician that RHS is likely if there are TWI in leads V1 through V3 (5 points) or a combination of an S wave in lead I and tachycardia (2 points + 3 points, respectively). These patients may benefit from close monitoring and further testing. Conversely, patients with a low TwiST score (≤2 points) are unlikely to have RHS, so clinicians may chose to limit testing in these patients.
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Clin. Cardiol. 38, 4, 236–242 (2015) P. Hariharan et al: Right heart strain after acute PE Published online in Wiley Online Library (wileyonlinelibrary.com) DOI:10.1002/clc.22383 © 2015 Wiley Periodicals, Inc.
Our findings are consistent with prior research. In our study, 50% of patients had evidence of RHS, similar to the results of previous studies.17,18 We found that the strongest ECG variable associated with RHS was the presence of TWI in leads V1 through V3 . Previous studies have shown that normalization of TWI in leads V1 through V3 is associated with recovery of RV dysfunction,19,20 and TWI in leads V1 through V3 is accurate for early detection of RV
dysfunction.10,20,21 This could be mechanistically explained by RV subendocardial ischemia during the acute PE event, as noted in animal models.21,22 Tachycardia is one of the more common ECG findings in acute PE and reflects hemodynamic compensation to reduced RV stroke volume. The S wave in lead I is likely the manifestation of rightward axis deviation in acute PE. The ECG score developed by Daniel et al also appears accurate, but it is more complex than the TwiST score to integrate into bedside practice. Moreover, the cutoff suggested in the publication by Daniel et al (>10 points) captured a relatively low percentage of our patients (n = 18, 6%), and though highly specific (97%), it was insensitive (9%) for RHS in our population.10 However, using alternative cutoffs of a score of ≤2 points (n = 134, 46%) and ≥7 points (n = 45, 16%), test characteristics improved, with sensitivity and specificity of 62% and 93%, respectively. In comparison, the TwiST score is more sensitive, characterizes a greater proportion of patients as either low or high risk, and is simpler to use. We also compared the strength of association of the TwiST and Daniel et al ECG scores with short-term adverse clinical events. This outcome is patient-centered and directly relevant to risk stratification after acute PE. We found that, using the same cutoffs, the TwiST score was sensitive and specific for adverse clinical events. These findings are consistent with a prior study looking at relationship of RHS pattern on ECG with adverse clinical events, where RHS on ECG added an incremental prognostic value to echocardiography in identifying high-risk patients.8 Study Limitations Our study has certain limitations as an observational prospective cohort study. Echocardiogram results were available in 40% of subjects with acute PE. However, 97% of subjects had CTPA measurements of RV strain, and all patients had Tn results. We acknowledge that we may be overestimating the proportion of patients with RHS. In subjects with no echocardiogram results (n = 173), 66 (38%) subjects had RHS based alone on CTPA. We also found 23 (23/58, 40%) of patients who had a positive CT for RHS had a negative echocardiogram. If this percentage were also true for patients who did not have echocardiograms, an extra 26 (26/146, or 18%) patients would be defined as having RHS based on CT data alone. However, because the goal of our study was to help clinicians identify patients who might need echocardiography using a simple ECG score, we think this conservative approach is reasonable. We did not exclude patients with other comorbidities (eg, chronic obstructive pulmonary disease) that could affect the ECG pattern and mimic RV strain. However, only 5% of the enrolled subjects had concomitant chronic obstructive pulmonary disease, so the presence of chronic lung disease is unlikely to have had a major effect on our results. Our findings may not completely reflect the accuracy of the Daniel score, as we modified the score, dichotomizing TWI as either present or absent rather than quantifying the depth of inversion as in the manuscript.10 The TwiST score has been formulated from this derivation cohort, and to ensure consistent test characteristics for RHS and adverse clinical outcomes, the
next step would be to test this association in an external validation dataset.
Conclusion A simple clinical ECG score, the TwiST score, can stratify patients with acute PE with regard to their risk of RHS and short-term adverse clinical events. This score may be useful to clinicians in determining prudent use of echocardiography or other imaging for risk stratification. Further research should be undertaken to identify the appropriate use of ECG findings in PE risk-stratification models.
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Heit JA. The epidemiology of venous thromboembolism in the community. Arterioscler Thromb Vasc Biol. 2008;28:370–372. Becattini C, Agnelli G. Predictors of mortality from pulmonary embolism and their influence on clinical management. Thromb Haemost. 2008;100:747–751. Jaff MR, McMurtry MS, Archer SL, et al. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association [published corrections appear in Circulation. 2012;125:e495 and Circulation. 2012;126:e104]. Circulation. 2011;123:1788–1830. Aujesky D, Obrosky DS, Stone RA, et al. Derivation and validation of a prognostic model for pulmonary embolism. Am J Respir Crit Care Med. 2005;172:1041–1046. Cheng AS, Money-Kyrle A. Instructive ECG series in massive bilateral pulmonary embolism. Heart. 2005;91:860–862. Choi BY, Park DG. Normalization of negative T-wave on electrocardiography and right ventricular dysfunction in patients with an acute pulmonary embolism. Korean J Intern Med. 2012;27:53–59. ´ O, Perez-de-Llano ´ Golpe R, Castro-A˜ non LA, et al. Electrocardiogram score predicts severity of pulmonary embolism in hemodynamically stable patients. J Hosp Med. 2011;6:285–289. Kukla P, Dlstrok;ugopolski R, Krupa E, et al. Electrocardiography and prognosis of patients with acute pulmonary embolism. Cardiol J. 2011;18:648–653. Daniel KR, Courtney DM, Kline JA. Assessment of cardiac stress from massive pulmonary embolism with 12-lead ECG. Chest. 2001;120:474–481. Jones AE, Kline JA. Availability of technology to evaluate for pulmonary embolism in academic emergency departments in the United States. J Thromb Haemost. 2003;1:2240–2242. von Elm E, Altman DG, Egger M, et al; STROBE Initiative. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. PLoS Med. 2007;4:e296. Sostman HD, Stein PD, Gottschalk A, et al. Acute pulmonary embolism: sensitivity and specificity of ventilation-perfusion scintigraphy in PIOPED II study. Radiology. 2008;246:941–946. Rudski LG, Lai WW, Afilalo J, et al. Guidelines for the echocardiographic assessment of the right heart in adults: a report from the American Society of Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography. J Am Soc Echocardiogr. 2010;23:685–713. George E, Kumamaru KK, Ghosh N, et al. Computed tomography and echocardiography in patients with acute pulmonary embolism: part 2: prognostic value. J Thorac Imaging. 2014;29:W7–W12. Hariharan P, Takayesu JK, Kabrhel C. Association between the Pulmonary Embolism Severity Index (PESI) and short-term clinical deterioration [published correction appears in Thromb Haemost. 2012;107:599]. Thromb Haemost. 2011;105:706–711. ´ Jimenez D, Aujesky D, Moores L, et al. Simplification of the pulmonary embolism severity index for prognostication in patients with acute symptomatic pulmonary embolism. Arch Intern Med. 2010;170:1383–1389.
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Address for correspondence: Christopher Kabrhel, MD Center for Vascular Emergencies Department of Emergency Medicine Massachusetts General Hospital Zero Emerson Place, Suite 3B Boston, MA 02114 [email protected]
Praveen Hariharan, MBBS, MPH; David M. Dudzinski, MD, JD; Ikenna Okechukwu, MD; James Kimo Takayesu, MD, MS; Yuchiao Chang, PhD; Christopher Kabrhel, MD, MPH Center for Vascular Emergencies, Department of Emergency Medicine (Hariharan, Okechukwu, Takayesu, Kabrhel), Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Division of Cardiology (Dudzinski), Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Department of Medicine (Chang), Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
Background: Electrocardiographic (ECG) changes may be seen with pulmonary emboli (PE). Whether ECG is associated with short-term adverse clinical events after PE is less well established. Hypothesis: ECG findings are associated with short-term clinical deterioration after PE. Methods: Consecutive adult PE patients were enrolled in an academic emergency department from 2008 to 2011. The primary outcome was right heart strain (RHS) on echocardiogram or CT pulmonary angiography, or TnT ≥0.1 ng/mL. We derived an ECG (TwiST) score that is associated with RHS and short-term adverse clinical events. Results: We enrolled 298 patients with PE. On multivariate analysis, T-wave inversion in leads V1 through V3 (OR: 4.7, 95% confidence interval [CI]: 1.7-13.2), S wave in lead I (OR: 2.0, 95% CI: 1.1-3.5), and tachycardia (OR: 2.5, 95% CI: 1.3-4.8) were associated with RHS. A TwiST score ≤2 (n = 210, 72%) was 84% (95% CI: 77%-90%) sensitive for the absence of RHS, whereas a TwiST score ≥5 (n = 47, 16%) was 93% (95% CI: 88%-97%) specific for the presence of RHS. Conclusions: A simple ECG (TwiST) score can identify patients likely or not likely to have RHS with >80% specificity and sensitivity and may assist in identifying patients with acute PE at risk for adverse clinical events before pursuing other advanced imaging tests.
Introduction Acute pulmonary embolism (PE) is a major health problem, accounting for >250 000 hospitalizations in the United States every year.1 The clinical outcome of acute PE varies widely, from mild symptoms and no hemodynamic consequences to cardiovascular collapse and respiratory failure.2 The American Heart Association (AHA) consensus guidelines recommend risk stratification of PE patients to guide appropriate and timely management and disposition.3
This study was funded by an award from the Harvard Milton Fund. The funding agency had no influence on the design or conduct of the study and played no role in interpreting the results or drafting the manuscript. This work was presented at the American College of Cardiology Scientific Sessions, Washington, DC, 2014. The authors have no other funding, financial relationships, or conflicts of interest to disclose. Additional Supporting Information may be found in the online version of this article.
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Risk stratification of PE involves weighing various risk predictors including age, demographics, comorbidities, and physical examination findings, as well as cardiac biomarkers and advanced cardiac imaging.4 Although the electrocardiogram (ECG) is inexpensive and universally performed in patients with PE, it is seldom incorporated into risk-stratification models. It is estimated that 70% of PE patients have abnormal ECG recordings.5 Certain ECG findings with PE may suggest right heart strain (RHS) and therefore might be used to prioritize care in these high-risk patients.6 – 9 As echocardiography is not routinely available during all hours of the day in many medical centers,10 ECG could be a useful tool for risk-stratifying PE patients. Electrocardiographic findings have been shown to correlate with the right ventricular (RV) strain and severe pulmonary hypertension after PE.7,10 However, ECG-based scores have not been directly validated against short-term adverse clinical events occurring during a typical postPE hospitalization. We sought to determine whether ECG findings are associated with RHS and short-term adverse clinical events after PE. Received: August 13, 2014 Accepted with revision: December 4, 2014
Methods Design We performed this study at Massachusetts General Hospital, an urban university hospital with an annual emergency department (ED) volume of 95 000 patient visits. We prospectively enrolled adult (age ≥18 years) ED patients diagnosed with radiographically proven PE between October 2008 and December 2011. We conducted the study in accordance with the published Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement.11 We used 2 methods for identifying consecutive patients with PE: (1) ED research staff screened for patients in the ED for 16 hours per day (from 7 AM to 11 PM) during weekdays; and (2) every morning a list of patients who had undergone computed tomography pulmonary angiography (CTPA) and ventilation/perfusion (V/Q) scans was generated and screened to identify patients who presented to the ED within the last 24 hours. These 2 complementary methods allowed us to enroll consecutive patients on all days except Saturday. Trained research staff using a standard form collected data. The Human Research Committee of Partners Healthcare approved the study. Subject Eligibility All PE patients diagnosed within 24 hours of ED registration who could provide informed consent were deemed eligible for the study. Subjects transferred from outside facilities to the ED with PE were eligible if they were enrolled in the study within 24 hours of diagnosis. Pulmonary embolism was diagnosed by either (1) a CTPA of the chest showing a filling defect in a pulmonary artery; (2) a computed tomography (CT) venogram, performed in conjunction with a CTPA in a patient with symptoms of PE (chest pain or dyspnea), showing a filling defect in a proximal deep vein of the leg consistent with deep-vein thrombosis; (3) positive venous ultrasound of an extremity consistent with deep-vein thrombosis in a patient with symptoms of PE (chest pain or dyspnea) who was subsequently treated for presumed PE; or (4) a V/Q scan read as high-probability for PE according to the Prospective Investigation of Pulmonary Embolism Diagnostic (PIOPED) criteria.12 Board-certified radiologists interpreted all radiographic findings as part of routine clinical care. Patients were excluded if they were age 100 bpm. SIQIIITIII was defined as presence of any S wave in lead I, Q wave (>1.5 mm deep) in lead III, and any TWI in lead III. A RBBB was defined as QRS duration >120 ms with terminal R wave in lead V1 and terminal S wave in lead I and V6 . Incomplete RBBB was defined as a QRS duration 100 to 120 ms and morphology otherwise similar to RBBB. We defined ST elevations, ST depressions, and TWI as either present or absent in each lead, but we did not quantify the magnitude of these deflections. We assessed the association of these ECG findings with RHS and adverse clinical events. We also determined the association of the ECG score published by Daniel et al10 with RHS and adverse clinical events in the patients in our cohort. In brief, the score by Daniel et al is a 21-point scoring system that includes tachycardia, incomplete and complete RBBB, depth of TWI on anterior ECG leads, and SIQIIITIII pattern.10 Primary Outcome Right Heart Strain: We defined RHS based on any 1 of the following: echocardiography, CTPA, or biomarker results. Diagnostic imaging (CPTA and echocardiography) were performed at the discretion of the treating physician. All echocardiograms were performed in accordance with the recommendations of the American Society of Echocardiography within 3 days of diagnosis of PE.13 Right ventricular (RV) strain was confirmed by the presence of RV hypokinesia, dilatation, and abnormal interventricular septum movement.14 In CTPA, a right ventricle/left ventricle (RV/LV) ratio >1 was considered positive for RV strain. Assay of troponin-T (Troponin-T STAT, COBAS 6000-CE, Roche, Indianapolis, IN, USA) was considered positive at ≥0.1 ng/dL. When an echocardiogram was not performed for clinical purposes, it was considered negative for the purposes of this analysis. When echocardiogram or Tn results were positive, a subject was deemed to have RHS. When echocardiogram results were not available and Tn was negative, then RHS was considered present if the RV/LV ratio was >1 on CTPA. Secondary Outcome and Subanalysis Our secondary outcome was designed to identify patients who suffer adverse clinical events within 5 days of diagnosis of PE (see Supporting Table 1 in the online version of this article).15 This timeframe was chosen based on prior literature and is consistent with a typical length of hospitalization for PE.16 Statistical Analysis Baseline data were reported as mean ± SD for continuous variables and as simple proportions for categorical variables. Univariate and sensitivity analysis were performed using ECG findings for our primary outcome of RHS. The association between ECG findings and RHS was summarized using test characteristics (sensitivity, specificity, odds ratios [ORs]) and examined using χ2 tests. Subsequently, Clin. Cardiol. 38, 4, 236–242 (2015) P. Hariharan et al: Right heart strain after acute PE Published online in Wiley Online Library (wileyonlinelibrary.com) DOI:10.1002/clc.22383 © 2015 Wiley Periodicals, Inc.
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we performed a multivariate analysis using the ECG findings revealing highest association from the univariate analysis and formulated a new ECG score. We used the new ECG score to obtain test characteristics at different cutoffs, and for our primary and secondary outcome in all patients. We performed a similar analysis with the ECG score by Daniel et al.10 Because the presence of chronic cor pulmonale and coronary artery disease (CAD) can be associated with ECG changes similar to those seen in acute PE, we performed a subanalysis of the ECG score excluding patients with a prior history of chronic lung disease and CAD. We also performed a subanalysis reclassifying patients (n = 23) who had RHS on CT but negative echocardiograms as not having RHS. The SAS software version 9.3 (SAS Institute Inc., Cary, NC) was used for all analyses.
Table 1. Characteristics of Enrolled Patients Characteristic Mean age, y
59 ± 17
Male sex
147 (51)
Race White
261 (90)
Black
17 (6)
Asian
3 (1)
Other
9 (3)
Ethnicity Non-Hispanic
Results We identified 403 consecutive patients with PE, and enrolled 301. The most common reasons patients were not enrolled were presentation on Saturday (n = 39), patient declined enrollment (n = 28), and inability to understand consent (n = 17) due to language or altered mental status. An ED ECG was available for review in 290 (97%) subjects, and these patients were included in our analysis. Radiologic and biomarker testing included CTPA (280/290, 97%), V/Q (4/290, 1%), lower-extremity ultrasound (94/290, 32%), CT venography (132/290, 46%), echocardiography (117/290, 40%), and Tn (290/290, 100%). Table 1 describes baseline characteristics of patients included in the analysis. Mean age was 59 ± 17 years; 51% were male and 90% described themselves as white. Notably, 36% (105 patients) had a history of malignancy. One hundred forty-six (50%) patients had RHS. Among patients with RHS, 51 (35%) were identified based on echocardiographic findings, 127 (87%) based on CTPA, and 12 (8%) based on a positive Tn. A positive Tn was noted in 1 subject with renal insufficiency (n = 8), 2 subjects with history of CAD (n = 26), and 1 subject history of congestive heart failure (n = 12). None of the enrolled subjects had concomitant acute coronary syndrome or acute congestive heart failure. Table 2 describes the univariate analysis of ECG characteristics for RHS. An S wave in lead I was the most common finding (81, 28%), followed by TWI in lead III (79, 27%) and HR >100 (58, 20%). An S wave in lead I, TWI in lead V1 through V2 , TWI in lead V1 through V3 , tachycardia, and incomplete RBBB were significantly associated with RHS. The classic SIQIIITIII finding was uncommon (15, 5%). Table 3 describes the results from the multivariable logistic regression model. Electrocardiographic patterns independently associated with the primary outcome were TWI in lead V1 through V3 (OR: 4.8, 95% confidence interval [CI]: 1.7-13.2), S wave in lead I (OR: 2.0, 95% CI: 1.1-3.5), and tachycardia (OR: 2.6, 95% CI: 1.4-4.8). Based on these results, we created a simple 10-point ECG score, the TwiST score, which includes TWI in leads V1 through V3 (5 points), S wave in lead I (2 points), and tachycardia (3 points). Table 4 shows the test characteristics of the TwiST ECG score for our primary outcome of RHS. In our cohort, 210 (72%) patients had a TwiST score ≤2 points, whereas 47
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Clin. Cardiol. 38, 4, 236–242 (2015) P. Hariharan et al: Right heart strain after acute PE Published online in Wiley Online Library (wileyonlinelibrary.com) DOI:10.1002/clc.22383 © 2015 Wiley Periodicals, Inc.
N (%) or ± SD
Hispanic
282 (97) 8 (3)
Comorbid Illness Asthma
25 (9)
COPD
14 (5)
CAD
26 (9)
CHF
12 (4)
Malignancy
105 (36)
Renal insufficiency/failure
8 (3)
Stroke or TIA
16 (6)
Prior VTE
59 (20)
Recent immobilization
70 (24)
Recent high-risk surgery
78 (27)
Abbreviations: CAD, coronary artery disease; CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; SD, standard deviation; TIA, transient ischemic attack; VTE, venous thromboembolism.
(16%) had a score ≥5 points. A TwiST score ≤2 points was 84% (95% CI: 77%-90%) sensitive for absence of RHS. A TwiST score ≥5 points was 93% (95% CI: 88%-97%) specific for RHS. When the TwiST ECG score was assessed against the rate of 5-day adverse clinical events (Table 4), the TwiST score ≤2 points was 76% (95% CI: 70%-81%) sensitive for absence of adverse clinical events, and a TwiST score ≥5 points, 87% (95% CI: 83%-91%) specific for adverse clinical events. Removing patients with a history of chronic lung disease and CAD did not change our results (data not shown). In our subanalysis reclassifying patients who had RHS on CT but negative echocardiograms as RHS negative, a TwiST score ≤2 points was 81% (95% CI: 74%-87%) sensitive for absence of RHS. A TwiST score ≥5 points was 91% (95% CI: 86%-95%) specific for RHS. Twenty-seven (9%) patients had severe outcome within 5 days of diagnosis of PE. Similarly in our cohort, 156 (54%) subjects had a Daniel et al ECG score ≤2 points as compared with 45 (16%) subjects ≥7 points. Table 5 shows the test characteristics of the Daniel et al score for our primary outcome of RHS. The Daniel et al ECG score ≤2 points was 62% (95% CI: 53%-70%)
Table 3. Multivariable Analysis of ECG Characteristics (TwiST Score) Table 2. Univariate Analysis of ECG Characteristics ECG Characteristics, N = 298
n (%)
OR (95% CI)
TWI in leads V1 through V2 a
41 (14)
2.11 (1.05-4.21)
TWI in leads V1 through V3 b
ECG Characteristics
Specificity, Sensitivity, % % 90
18
26 (9) 4.67 (1.71-12.76)
97
14
TWI in leads V1 through V4 c
12 (4) 2.03 (0.60-6.89)
97
5
S wave in lead Id
81 (28) 2.36 (1.39-4.02)
81
36
Tachycardia ≥100 bpm
58 (20) 2.64 (1.43-4.88)
88
27
Non–sinus rhythm 43 (15) 0.84 (0.44-1.60)
84
14
Q wave in lead IIIe
47 (16) 1.15 (0.61-2.14)
85
17
TWI in lead III
79 (27) 1.44 (0.86-2.43)
76
31
1.13 (0.40-3.22)
95
5
Incomplete RBBB
29 (10) 2.38 (1.05-5.42)
94
14
Complete RBBBg
13 (4)
97
6
SIQIIITIII pattern
15 (5) f
2.30 (0.69-7.64)
Abbreviations: CI, confidence interval; ECG, electrocardiogram; OR, odds ratio; RBBB, right bundle branch block; RHS, right heart strain; TWI, T-wave inversion. Sensitivity and specificity calculated for RHS. a TWI in leads V1 and V2 . b TWI in leads V1 , V2 , and V3 . c TWI in leads V1 , V2 , V3 , and V4 . d First negative deflection after R wave >1.5 mm. e First negative deflective after P waves of size >1.5 mm before any R wave. f 100 msec < QRS length < 120 msec with terminal R wave in lead V1 and terminal S wave in leads I and V6 . g QRS length > 120 msec with terminal R wave in lead V1 and terminal S wave in leads I and V6 .
TWI in leads V1 through V3
n (%) a
OR (95% CI)
P Value Points
26 (9) 4.76 (1.71-13.28)
0.003
5
S wave in lead I
81 (28) 2.04 (1.17-3.54)
0.012
2
Tachycardia ≥100 bpm
58 (20) 2.58 (1.37-4.85)
0.003
3
Abbreviations: CI, confidence interval; ECG, electrocardiogram; OR, odds ratio; TWI, T-wave inversion. Point value has been assigned to each ECG characteristic based on the parameter estimate (β) from the univariate analysis. a TWI in leads V1 , V2 , and V3 .
sensitive for absence of RHS. A Daniel et al ECG score ≥7 points was 93% (95% CI: 88%-97%) specific for RHS. When the Daniel et al ECG score was assessed for secondary outcomes (Table 5), the ECG score ≤2 points was 57% (95% CI: 50%-63%) sensitive for absence of adverse clinical events and a score ≥7 points was 87% (95% CI: 83%-91%) specific for adverse clinical events.
Discussion Electrocardiography is one of the first diagnostic tests performed for patients presenting with symptoms of PE. The AHA recommends risk stratification of acute PE patients based on RHS.3 Certain ECG characteristics have been shown to be associated with RHS but typically are not incorporated in the risk-stratification models.4,16 In this study, we found 3 ECG characteristics independently associated with RHS: TWI in leads V1 through V3 , S wave in lead I, and sinus tachycardia. We derived a simple, easyto-use, 10-point ECG score that can effectively risk-stratify 85% of acute PE patients. A TwiST ECG score ≤2 points can exclude RHS with 85% sensitivity, whereas a score of ≥5 points is 93% specific for RHS in patients with PE. The
Table 4. Test Characteristics of TwiST ECG Score at Different Cutoffs for RHS ECG Score Cutoff Points
n (%)
Sensitivity, % (95% CI)
Specificity, % (95% CI)
PPV, % (95% CI)
NPV, % (95% CI)
≤2 points
210 (72)
84 (77–90)
39 (31–47)
58 (51–64)
71 (60–81)
≥3 points
80 (28)
39 (31–47)
84 (77–90)
71 (60–81)
58 (51–64)
≥5 points
47 (16)
25 (19–33)
93 (88–97)
79 (64–89)
55 (49–62)
≥7 points
12 (4)
8 (4–14)
100 (97–100)
100 (74–100)
52 (46–58)
≥8 points
4 (1)
3 (1–7)
100 (97–100)
100 (40–100)
50 (44–56)
Score at cutoffs for RHS
Score at cutoffs for clinical deterioration ≤2 points
210 (72)
76 (70–81)
59 (39–78)
95 (91–97)
20 (12–30)
≥3 points
80 (28)
59 (39–78)
76 (70–81)
20 (12–30)
95 (91–97)
≥5 points
47 (16)
52 (32–71)
87 (83–91)
30 (17–45)
95 (91–97)
≥7 points
12 (4)
11 (2–29)
97 (94–98)
25 (5–57)
91 (87–94)
≥8 points
4 (1)
4 (0–19)
99 (97–100)
25 (1–81)
91 (87–94)
Abbreviations: CI, confidence interval; ECG, electrocardiogram; NPV, negative predictive value; OR, odds ratio; PPV, positive predictive value; RHS, right heart strain. Clin. Cardiol. 38, 4, 236–242 (2015) P. Hariharan et al: Right heart strain after acute PE Published online in Wiley Online Library (wileyonlinelibrary.com) DOI:10.1002/clc.22383 © 2015 Wiley Periodicals, Inc.
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Table 5. Test Characteristics of Daniel et al ECG Score at Different Cutoffs for RHS ECG Score Cutoff Points
n (%)
Sensitivity, % (95% CI)
Specificity, % (95% CI)
PPV, % (95% CI)
NPV, % (95% CI)
≤2 points
156 (54)
62 (53–70)
54 (46–62)
57 (49–65)
59 (50–67)
≥3 points
134 (46)
54 (46–62)
62 (53–70)
59 (50–67)
57 (49–65)
≥4 points
99 (34)
41 (33–50)
73 (65–80)
61 (50–70)
55 (48–62)
≥5 points
79 (27)
34 (26–42)
79 (72–85)
62 (50–73)
54 (47–61)
≥6 points
58 (20)
27 (20–35)
88 (81–92)
69 (55–80)
54 (48–61)
≥7 points
45 (16)
24 (17–32)
93 (88–97)
78 (63–89)
55 (48–61)
≥8 points
39 (13)
21 (15–29)
94 (89–98)
79 (64–91)
54 (48–60)
≥9 points
31 (11)
16 (11–23)
95 (90–98)
77 (59–90)
53 (47–59)
≥10 points
20 (7)
10 (6–16)
97 (92–99)
75 (51–91)
51 (45–58)
≥11 points
18 (6)
9 (5–15)
97 (92–99)
72 (47–90)
51 (45–57)
≥12 points
15 (5)
7 (3–12)
97 (92–99)
67 (38–88)
51 (44–57)
≥13 points
12 (4)
5 (2–10)
97 (92–99)
58 (28–85)
50 (44–56)
≥14 points
5 (2)
3 (1–7)
99 (96–100)
80 (28–99)
50 (44–56)
≥18 points
3 (1)
2 (0–6)
100 (97–100)
100 (29–100)
50 (44–56)
Score at cutoffs for RHS
Score at cutoffs for severe clinical outcomes ≤2 points
156 (54)
57 (50–63)
74 (54–89)
96 (91–98)
15 (9–22)
≥3 points
134 (46)
74 (54–89)
57 (50–63)
15 (9–22)
96 (91–98)
≥4 points
99 (34)
56 (35–75)
68 (62–74)
15 (9–24)
94 (89–97)
≥5 points
79 (30)
48 (29–68)
75 (69–80)
16 (9–26)
93 (89–96)
≥6 points
58 (20)
44 (25–65)
83 (77–87)
21 (11–33)
94 (90–96)
≥7 points
45 (16)
44 (25–65)
87 (83–91)
27 (15–42)
94 (90–97)
≥8 points
39 (13)
37 (19–58)
89 (85–92)
26 (13–42)
93 (89–96)
≥9 points
31 (11)
33 (17–54)
92 (88–95)
29 (14–48)
93 (89–96)
≥10 points
20 (7)
15 (4–34)
94 (90–96)
20 (6–44)
91 (87–95)
≥11 points
18 (6)
15 (4–34)
95 (91–97)
22 (6–48)
92 (88–95)
≥12 points
15 (5)
11 (2–29)
95 (92–98)
20 (4–48)
91 (87–94)
≥13 points
12 (4)
7 (1–24)
96 (93–98)
17 (2–48)
91 (87–94)
≥14 points
5 (2)
4 (0–19)
98 (96–100)
20 (1–72)
91 (87–94)
≥18 points
3 (1)
4 (0–19)
99 (97–100)
33 (1–91)
91 (87–94)
Abbreviations: CI, confidence interval; ECG, electrocardiogram; NPV, negative predictive value; OR, odds ratio; PPV, positive predictive value; RHS, right heart strain.
optimal use of the TwiST score in clinical practice may be to alert the clinician that RHS is likely if there are TWI in leads V1 through V3 (5 points) or a combination of an S wave in lead I and tachycardia (2 points + 3 points, respectively). These patients may benefit from close monitoring and further testing. Conversely, patients with a low TwiST score (≤2 points) are unlikely to have RHS, so clinicians may chose to limit testing in these patients.
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Clin. Cardiol. 38, 4, 236–242 (2015) P. Hariharan et al: Right heart strain after acute PE Published online in Wiley Online Library (wileyonlinelibrary.com) DOI:10.1002/clc.22383 © 2015 Wiley Periodicals, Inc.
Our findings are consistent with prior research. In our study, 50% of patients had evidence of RHS, similar to the results of previous studies.17,18 We found that the strongest ECG variable associated with RHS was the presence of TWI in leads V1 through V3 . Previous studies have shown that normalization of TWI in leads V1 through V3 is associated with recovery of RV dysfunction,19,20 and TWI in leads V1 through V3 is accurate for early detection of RV
dysfunction.10,20,21 This could be mechanistically explained by RV subendocardial ischemia during the acute PE event, as noted in animal models.21,22 Tachycardia is one of the more common ECG findings in acute PE and reflects hemodynamic compensation to reduced RV stroke volume. The S wave in lead I is likely the manifestation of rightward axis deviation in acute PE. The ECG score developed by Daniel et al also appears accurate, but it is more complex than the TwiST score to integrate into bedside practice. Moreover, the cutoff suggested in the publication by Daniel et al (>10 points) captured a relatively low percentage of our patients (n = 18, 6%), and though highly specific (97%), it was insensitive (9%) for RHS in our population.10 However, using alternative cutoffs of a score of ≤2 points (n = 134, 46%) and ≥7 points (n = 45, 16%), test characteristics improved, with sensitivity and specificity of 62% and 93%, respectively. In comparison, the TwiST score is more sensitive, characterizes a greater proportion of patients as either low or high risk, and is simpler to use. We also compared the strength of association of the TwiST and Daniel et al ECG scores with short-term adverse clinical events. This outcome is patient-centered and directly relevant to risk stratification after acute PE. We found that, using the same cutoffs, the TwiST score was sensitive and specific for adverse clinical events. These findings are consistent with a prior study looking at relationship of RHS pattern on ECG with adverse clinical events, where RHS on ECG added an incremental prognostic value to echocardiography in identifying high-risk patients.8 Study Limitations Our study has certain limitations as an observational prospective cohort study. Echocardiogram results were available in 40% of subjects with acute PE. However, 97% of subjects had CTPA measurements of RV strain, and all patients had Tn results. We acknowledge that we may be overestimating the proportion of patients with RHS. In subjects with no echocardiogram results (n = 173), 66 (38%) subjects had RHS based alone on CTPA. We also found 23 (23/58, 40%) of patients who had a positive CT for RHS had a negative echocardiogram. If this percentage were also true for patients who did not have echocardiograms, an extra 26 (26/146, or 18%) patients would be defined as having RHS based on CT data alone. However, because the goal of our study was to help clinicians identify patients who might need echocardiography using a simple ECG score, we think this conservative approach is reasonable. We did not exclude patients with other comorbidities (eg, chronic obstructive pulmonary disease) that could affect the ECG pattern and mimic RV strain. However, only 5% of the enrolled subjects had concomitant chronic obstructive pulmonary disease, so the presence of chronic lung disease is unlikely to have had a major effect on our results. Our findings may not completely reflect the accuracy of the Daniel score, as we modified the score, dichotomizing TWI as either present or absent rather than quantifying the depth of inversion as in the manuscript.10 The TwiST score has been formulated from this derivation cohort, and to ensure consistent test characteristics for RHS and adverse clinical outcomes, the
next step would be to test this association in an external validation dataset.
Conclusion A simple clinical ECG score, the TwiST score, can stratify patients with acute PE with regard to their risk of RHS and short-term adverse clinical events. This score may be useful to clinicians in determining prudent use of echocardiography or other imaging for risk stratification. Further research should be undertaken to identify the appropriate use of ECG findings in PE risk-stratification models.
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