Relation of Atrial Fibrillation and Right-Sided Cardiac Thrombus to Outcomes in Patients With Acute Pulmonary Embolism Piotr Kukla, MD, PhDa,*, Wiliam F. McIntyre, MDb, Goran Koracevic, MD, PhDc, Dusanka Kutlesic-Kurtovic, MDc, Kamil Fijorek, MScd, Vesna Atanaskovic, MDc, Ewa Krupa, MDe, Ewa Mirek-Bryniarska, MD, PhDf, Marek Jastrze˛ bski, MD, PhDg, Leszek Bryniarski, MD, PhDg, Piotr Pruszczyk, MD, PhDh, and Adrian Baranchuk, MDi Atrial fibrillation (AF) can induce a hypercoagulable state in both the left and right atria. Thrombus in the right side of the heart (RHT) may lead to acute pulmonary embolism (APE). The aim of the study was to determine the prevalence of RHT and AF and to assess their impact on outcomes in patients with APE. The retrospective cohort included 1,006 patients (598 female), with a mean age of 66 – 15 years. The primary end point was allcause mortality. The secondary end point was incidence of complications (death, cardiogenic shock, cardiac arrest, vasopressor/inotrope treatment, or ventilatory support). Atrial fibrillation was detected in 231 patients (24%). RHT was observed in 50 patients (5%). The combination of AF and RHT was observed in 16 patients (2%). The overall mortality rate was significantly higher in patients with RHT compared with those without (32% vs 14%, respectively, odds ratio [OR] 3.0, 95% confidence interval [CI] 1.6 to 5.6, p [ 0.001). The rate of complications was significantly higher in patients with RHT in comparison to those without (40% vs 22%, respectively, OR 2.4, 95% CI 1.3 to 4.4, p [ 0.004). The mortality rate in patients with both AF and RHT was significantly higher in comparison to those with AF but without RHT (50% vs 20%, respectively, OR 3.86, 95% CI 1.3 to 11.2, p [ 0.01). In multivariate analysis, RHT (p [ 0.03) was an independent predictor of death. In conclusion, AF is a frequent co-morbidity in patients with APE, and the presence of RHT is not uncommon. Among patients with APE, the presence of RHT increases the mortality approximately threefold regardless of the presence of known AF. Ó 2015 Elsevier Inc. All rights reserved. (Am J Cardiol 2015;115:825e830) The association between ischemic stroke and systemic emboli arising from left atrial thrombus in patients with atrial fibrillation (AF) is well described. The notion of a parallel right atrial process leading to pulmonary venous thromboemboli has also been proposed.1 This theory can be supported by the observation of spontaneous echocardiographic contrast in both atria in patients with right-sided cardiac abnormalities, including AF.2,3 Where it has been

a Department of Internal Medicine and Cardiology, Specialistic Hospital, Gorlice, Poland; bSection of Cardiology, Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada; cDepartment for Cardiovascular Diseases, Clinical Center, Nis, Serbia; dDepartment of Statistics, Cracow University of Economics, Cracow, Poland; eDepartment of Cardiology, Szczeklik Specialistic Hospital, Tarnów, Poland; fDepartment of Cardiology, Dietl Specialistic Hospital, Cracow, Poland; gFirst Department of Cardiology, Interventional Electrocardiology and Hypertension, Jagiellonian University, Cracow, Poland; hDepartment of Internal Medicine and Cardiology, Medical University of Warsaw, Poland; and i Division of Cardiology, Kingston General Hospital, Queen’s University, Kingston, Ontario, Canada. Manuscript received October 29, 2014; revised manuscript received and accepted December 23, 2014. See page 829 for disclosure information. *Corresponding author: Tel: (þ48) 18 35 53 417; fax: (þ48) 18 352 60 46. E-mail address: [email protected] (P. Kukla).

0002-9149/15/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2014.12.049

shown that the presence of AF provokes a hypercoagulable state and induces platelet aggregation,4e6 it would seem sensible to infer that the hypercoagulable state exists in both the right and left atria. Reports that predate the era of widespread anticoagulation for patients with AF indicate that thrombus can develop in the right atrium. The landmark autopsy study by Aberg in 693 consecutive patients with AF showed that 13% of patients had clots in the left atrium and 8% had clots in the right atrium and that these occurred predominantly in the appendages.7 The risk stratification of patients with acute pulmonary embolism (APE) remains a challenge.8e10 Exploration of the link between APE, AF, and right heart thrombus (RHT) may provide further information about the pathophysiology of these disease processes and aid in risk stratification for patients with APE. The aim of this study was to determine the prevalence of RHT and AF and to assess their impact on outcomes in patients with APE. Methods This was a retrospective analysis of consecutive patients who were diagnosed with APE and were hospitalized in the cardiology departments of 8 community hospitals in 2 countries from 2004 to 2012. All clinical data were collected at the time admission or at the first occurrence during the www.ajconline.org

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The American Journal of Cardiology (www.ajconline.org)

Figure 1. Patient enrollment flowchart. CT ¼ computed tomography.

Table 1 Characteristics of a study population of patients with acute pulmonary embolism Variable Age (years) Women Atrial Fibrillation Pattern of Atrial Fibrillation Paroxysmal Permanent Fibrinolysis Syncope Chest pain Chronic obstructive pulmonary disease Heart failure Obesity Cancer Active infection Immobilization Deep Venous Thrombosis Systolic blood pressure* [mmHg] Diastolic blood pressure* [mmHg]

Overall (n¼ 975)

Right-Sided Heart Thrombus (-) (n¼925)

Right-Sided Heart Thrombus (þ) (n¼50)

OR [95% CI]

p-value

65.8 (14.7) 576 (59%) 231 (24%)

65.9 (145) 547 (59%) 215 (23%)

64.4 (17) 29 (58%) 16 (33%)

0.9 [0.8-1.1] 1.0 [0.5-1.7] 1.6 [0.8-2.9]

0.5 09 0.1

60 169 82 215 434 93 116 184 126 122 218 371 124

55 158 72 204 418 90 110 177 119 115 199 355 125

5 11 10 11 16 3 6 7 7 7 19 16 108

2.0 [0.7-4.9] 1.5 [0.7-3.0] 3.0 [1.4-6.0] 1.0 [0.5-1.9] 0.6 [0.3-1.0] 0.6 [0.1-1.7] 1.0 [0.4-2.3] 0.7 [0.3-1.5] 1.1 [0.5-2.4] 1.2 [0.5-2.5] 2.2 [1.2-4.0] 0.8 [0.4-1.4] 0.9 [0.8-1.0] per 10 mmHg 0.9 [0.7-1.0] per 10 mmHg 1.1 [1.0-1.2] per 10 bpm 1.4 [0.6-3.5] 2.4 [1.3-4.4] 3.0 [1.6-5.6] 2.3 [1.0-4.5] 2.3 [1.1-4.3] 5.1 [1.8-21.8]

(6%) (17%) (8%) (22%) (45%) (10%) (12%) (19%) (13%) (13%) (22%) (38%) (32)

76 (19)

(56%) (17%) (8%) (22%) (45%) (10%) (12%) (19%) (13%) (12%) (22%) (39%) (31)

76.4 (9)

69.9 (29) 109 (22)

Heart Rate* [bpm]

101 (27)

101 (27)

Elevated cTnT* Vasopressors/Inotropes Death Catecholamines Shock Right Ventricular Overload*

340 219 141 105 126 661

323 (57%) 199 (22%) 125 (14%) 95 (10%) 114 (12%) 614 (75%)

(57%) (23%) (15%) (11%) (13%) (76%)

(10%) (22%) (20%) (22%) (32%) (6%) (12%) (14%) (14%) (14%) (38%) (33%) (48)

17 20 16 10 12 47

(65%) (40%) (32%) (20%) (24%) (94%)

0.2 0.3 0.009 1.0 0.07 0.404 0.9 0.4 0.8 0.7 0.01 0.4 0.004 0.07 0.04 0.4 0.004 0.001 0.04 0.03 0.001

* Missing data for systolic and diastolic BP w 30%, for HR w 15%, for cTnT w 38%, for RV overload w14%.

hospitalization. The presence of thrombus in the right atrium and ventricle was assessed by echocardiography or computed tomography with angiography (CTA). CTA was performed immediately when APE was suspected. Echocardiography

was performed as the primary diagnostic investigation when a patient was in cardiogenic shock, was experiencing chest pain, or after CTA when APE was confirmed. Transthoracic echocardiography was performed using dedicated

Miscellaneous/Pulmonary Embolism and Right Heart Thrombus

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Table 2 Mortality and complication rates in acute pulmonary embolism patients with atrial fibrillation according to presence or absence of thrombus in the right side of the heart Group

n

Mortality Rate

OR, [95 % CI]

Complication Rate

OR, [95% CI]

AF þ AF -

231 740

23% 12%

2.1 [1.4-3.0] p < 0.001

31% 20%

1.8 [1.3-2.5] p < 0.001

AF þ / RHT þ AF þ / RHT -

16 215

50% 20%

3.9 [1.3-11.2] p ¼ 0.01

56% 29%

3.1 [1.1-9.1] p ¼ 0.04

AF - / RHT þ AF - / RHT -

33 707

24% 11%

2.6 [1.0-5.7] p ¼ 0.04

33% 19%

2.2 [1.0-4.5] p ¼ 0.06

AF ¼ atrial fibrillation; CI ¼ confidence interval; OR ¼ odds ratio; RHT ¼ right-sided heart thrombus.

echocardiographic systems equipped with 3.5-MHz phased array probes. During echocardiographic examination, masses in the right side of the heart were reported as thrombi when their echodensity differed from the blood and heart structures or when these demonstrated their own pattern of motion. Poorly defined structures seen in the heart cavities were not reported as thrombi. Only CTA examinations with “good” image quality were interpreted. Thrombi were reported when filling defects with low attenuation and distinct borders surrounded by contrast medium were detected within the right side of the heart. Standard 12-lead surface electrocardiograms (ECGs) were recorded with a paper speed of 25 to 50 mm/s. The first available ECG was used for analysis. This ECG was assessed for the presence of AF. In 4 patients, the admission ECG was not of appropriate technical quality to assess for AF. All patients were divided into 2 subgroups according to the pattern of AF: (1) AF () group—patients without a known medical history of AF, in sinus rhythm on admission, and without detectable AF during the hospitalization and (2) AF (þ) group—patients with a known medical history of AF and those who were found to be in AF at some point during the hospital admission (paroxysmal, persistent, or permanent AF). Patients were further classified as paroxysmal or nonparoxysmal (persistent or permanent). Low blood pressure (BP) was defined as 90/60 mm Hg. Elevated heart rate (HR) was defined as 100 beats/min. HR on admission was defined as the HR assessed from ECG recorded on admission. Right ventricular overload was defined by the presence of at least one of the following echocardiographic parameters: right ventricular diameter 30 mm in the parasternal view or RV/LV ratio >1, acceleration time of right ventricular (RV) ejection 30 mm Hg without RV hypertrophy, paradoxical systolic movement of the septum, presence of hypokinesia or akinesia of the RV free wall, or presence of RHT. Obesity was defined as body mass index 30 kg/m2. The primary end point was all-cause mortality during the index hospitalization. The secondary end point was incidence of complications (a composite of death, cardiogenic shock, cardiac arrest, vasopressor/inotrope treatment, or mechanical ventilatory support). Categorical variables are expressed as numbers and percentages and continuous variables as means and SDs. The statistical significance of differences between 2 groups was assessed using a univariate logistic regression model in which

the direction and strength of an association between a grouping variable and a predictor were summarized by the odds ratio (OR) with a 95% confidence interval (CI). The multivariate logistic regression model, due to a noticeable fraction of data missing in few clinically relevant predictors, was estimated using the method of multiple imputation by chained equations (imputation model was random forests, 100 imputed data sets were created).11 A 2-tailed p value