Association between preexisting versus newly identified atrial fibrillation and outcomes of patients with acute pulmonary embolism

Journal of the American Heart Association J Am Heart Assoc. 2021;10:e021467. DOI: 10.1161/JAHA.121.021467 1 ORIGINAL RESEARCH Association Between Preexisting Versus Newly Identified Atrial Fibrillation and Outcomes of Patients With Acute Pulmonary Embolism Behnood Bikdeli , MD, MS*; David Jiménez , MD, PhD*; Jorge del Toro , MD; Gregory Piazza , MD, MS; Agustina Rivas, MD; José Luis Fernández- Reyes, MD; Ángel Sampériz, MD, PhD; Remedios Otero, MD, PhD; José María Suriñach, MD, PhD; Carmine Siniscalchi , MD, PhD; Javier Miguel Martín- Guerra, MD; Joaquín Castro , MD; Alfonso Muriel , PhD; Gregory Y. H. Lip , MD; Samuel Z. Goldhaber , MD; Manuel Monreal , MD, PhD; For the RIETE Investigators† BACKGROUND: Atrial fibrillation (AF) may exist before or occur early in the course of pulmonary embolism (PE). We determined the PE outcomes based on the presence and timing of AF. METHODS AND RESULTS: Using the data from a multicenter PE registry, we identified 3 groups: (1) those with preexisting AF, (2) patients with new AF within 2days from acute PE (incident AF), and (3) patients without AF. We assessed the 90- day and 1- year risk of mortality and stroke in patients with AF, compared with those without AF (reference group). Among 16497 patients with PE, 792 had preexisting AF. These patients had increased odds of 90- day allcause (odds ratio [OR], 2.81; 95% CI, 2.33– 3.38) and PE- related mortality (OR, 2.38; 95% CI, 1.37– 4.14) and increased 1- year hazard for ischemic stroke (hazard ratio, 5.48; 95% CI, 3.10– 9.69) compared with those without AF. After multivariable adjustment, preexisting AF was associated with significantly increased odds of allcause mortality (OR, 1.91; 95% CI, 1.57– 2.32) but not PE- related mortality (OR, 1.50; 95% CI, 0.85– 2.66). Among 16497 patients with PE, 445 developed new incident AF within 2days of acute PE. Incident AF was associated with increased odds of 90- day allcause (OR, 2.28; 95% CI, 1.75– 2.97) and PE- related (OR, 3.64; 95% CI, 2.01– 6.59) mortality but not stroke. Findings were similar in multivariable analyses. CONCLUSIONS: In patients with acute symptomatic PE, both preexisting AF and incident AF predict adverse clinical outcomes. The type of adverse outcomes may differ depending on the timing of AF onset. Key Words: atrial fibrillation ■ mortality ■ outcome ■ pulmonary embolism Pulmonary embolism (PE) is a thromboembolic disease with potentially serious or fatal complications.1– 3 Understanding the risk profile for patients with acute PE is critical, because timely assessment may help with risk stratification.4 Several tools exist for such risk assessment,5,6 including the simplified Pulmonary Embolism Severity Index (sPESI).7 Nevertheless, risk assessment remains suboptimal for several patient subgroups. Therefore, finding additional ways to predict adverse outcomes is crucial. Atrial fibrillation (AF) is a common arrhythmia,8 associated with increased rates of stroke, myocardial Correspondence to: Behnood Bikdeli, MD, MS, Cardiovascular Medicine Division, Brigham and Women’s Hospital, 75 Francis Street, Shapiro 5, Suite 5156. Boston, MA 02115. E- mail: [email protected]; [email protected] *B. Bikdeli and D. Jiménez contributed equally. †A full list of the RIETE Investigators can be found in the Appendix at the end of the article. Supplementary Material for this article is available at https://www.ahajo urnals.org/doi/suppl/ 10.1161/JAHA.121.021467 For Sources of Funding and Disclosures, see page 11. © 2021 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the Creative Commons Attribution- NonCommercial- NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is noncommercial and no modifications or adaptations are made. JAHA is available at: www.ahajournals.org/journal/jaha Downloaded from http://ahajournals.org by on December 15, 2022 J Am Heart Assoc. 2021;10:e021467. DOI: 10.1161/JAHA.121.021467 2 Bikdeli et al Preexisting vs Incident AF in Patients With PE infarction, and heart failure.9,10 The presence of AF may affect the thromboembolic and hemorrhagic risk across a wide spectrum of cardiovascular conditions. For example, investigations related to coexisting AF and coronary disease have led to tailored strategies to address the thrombotic risk.11– 13 The association between PE and AF has received recent attention.14,15 Presentations of AF occurring before15– 17 or early in the course of18 acute PE have been described. However, the majority of the prior studies of the AFPE association has been based on a small number of patients or on administrative data.15,19 Little is known about the comparative presentation and outcomes according to the time of AF onset with respect to PE. In addition, it remains unknown whether AF is merely a surrogate for cardiovascular risk, associated with increased allcause mortality, or if it is associated with PE- related mortality. Further, it is unclear whether the associations, if present, are because of differences in baseline characteristics or whether they persist after multivariable adjustment.15,20 Using the data from the RIETE (Registro Informatizado de Enfermedad Tromboembólica) registry, we sought to identify patients with PE and coexisting AF and profile their PE presentation, coexisting characteristics, treatment patterns, and outcomes according to the time course of AF. We focused on (1) preexisting AF diagnosed before the index PE event, and (2) new AF diagnosed within the first 2days of diagnosis of acute PE (incident AF). We considered patients with PE who did not have AF as referent. METHODS The methods implemented for the current study are summarized. Further details about the study methodology or the underlying data will be made available to interested investigators, upon submitting a reasonable research request to the principal investigators (B.B., D.J., and M.M.) and approval of the RIETE advisory committee. Data Source RIETE is a multicenter international registry of consecutive patients with objectively confirmed venous thromboembolism (VTE; deep vein thrombosis, PE, or splanchnic vein thrombosis). The methodology of the registry has been described previously.21 The protocol for patient enrollment was approved by the participating centers. Data were stored and audited by the RIETE coordinating center (S&H Medical Sciences Services, Madrid, Spain). All study participants provided informed consent, in accordance with local institutional review board criteria. For the current study, we included patients with PE from April 2, 2014 to January 31, 2020. This choice was made to include patients for whom data elements related to AF were available, while avoiding the inclusion of patients with VTE in the setting of the COVID- 19 pandemic.22,23 Patients Patients with acute symptomatic PE were considered for inclusion in this study. We excluded patients with asymptomatic PE. We hypothesized that patients with preexisting AF and patients with incident AF may each have different characteristics and outcomes compared with those without AF. However, because these differences may be epidemiologically and pathophysiologically distinct, we prespecified the analysis of these 2 subgroups of AF separately. For all analyses, patients without preexisting AF or incident AF were considered as referent. Patient Characteristics We assessed the demographics and comorbidities such as diabetes mellitus, hypertension, atherosclerotic vascular disease, chronic pulmonary disease, stroke, cancer, and recent surgery (ie, within 2months before enrollment in RIETE). Treatment patterns for each group, including anticoagulant therapy and CLINICAL PERSPECTIVE What Is New? • This study demonstrated that atrial fibrillation (AF) may exist before or occur early in the course of acute pulmonary embolism and lead to worse clinical outcomes, which may be dependent on the timing of the AF: preexisting AF predicts allcause mortality and 1- year risk of stroke whereas new (incident) AF predicts allcause mortality and pulmonary embolismrelated mortality. What Are the Clinical Implications? • The presence of coexisting AF in patients with pulmonary embolism is indicative of higher risk for adverse events and should be assessed in future studies to determine whether it improves risk stratification and can direct more optimal use of treatment strategies. Nonstandard Abbreviations and Acronyms RIETE Registro Informatizado de Enfermedad TromboEmbólica sPESI simplified Pulmonary Embolism Severity Index Downloaded from http://ahajournals.org by on December 15, 2022 J Am Heart Assoc. 2021;10:e021467. DOI: 10.1161/JAHA.121.021467 3 Bikdeli et al Preexisting vs Incident AF in Patients With PE advanced therapies (including fibrinolytic therapy and percutaneous or surgical thrombectomy) were evaluated. For patients who remained alive at followup, we explored within each group the proportion of patients who remained on anticoagulation at 90days and at 1- year followup. Outcomes The coprimary outcomes were PE- related mortality at 90 days from enrollment and allcause mortality at 1- year followup. The prespecified secondary end points were the 1- year rate of ischemic stroke and the composite of thrombotic events (consisting of myocardial infarction, ischemic stroke, or subsequent VTE). Other study end points included 90- day allcause mortality and 1- year PE- related mortality. Because we expected fewer shortterm events, in order to minimize the type I error rate, we prespecified that we would assess stroke, recurrent VTE, and also composite thrombotic end points only at 1- year followup. The main safety outcomes were major bleeding at 90- day and 1- year followup. Major bleeding was defined as events that required transfusion of ≥2units of blood or were retroperitoneal, spinal, intracranial, intrapericardial, or fatal. This definition closely resembles that of the International Society on Thrombosis and Haemostasis.24 In all analyses, patients without AF were considered as reference group. Statistical Analysis Categorical variables were reported as percentages. Continuous variables were reported as mean and standard error of the mean (or median and interquartile range, where not normally distributed). To minimize type I error, it was prespecified to avoid unselected pairwise hypothesis testing for the baseline characteristics between groups.25 We planned to report the relative frequencies for categorical variables with 99% CIs. Post hoc chi square tests were considered only if there were nonoverlapping 99% CIs of clinical relevance. For baseline numeric variables, to avoid inflation of the type I error, we prespecified to run tests of statistical comparisons only among the variables that reflected clinically meaningful differences (as decided by the study steering committee based on the magnitude of observed difference and expected difference based on clinical consensus), in addition to age and the sPESI, which were prespecified.7 No a priori power calculation was made for this study. In general, logistic regression models are more powerful and are less prone to statistical assumptions. As a unique strength of the registry, RIETE has complete 100% followup for all patients until 90days from the index VTE event or until death. Accordingly, for assessment of 90- day outcomes, we used logistic regression models for adjustment and reported odds ratio (OR) as the effect measure. For 1- year allcause mortality, we used Cox proportional hazard models and reported hazard ratios (HR) as the effect measure. For outcomes other than allcause mortality (ie, PE- related mortality, thrombosis composite outcome, and major bleeding), we used Fine- Gray hazard models that accounted for the competing risk of death from events other than the outcome of interest. Survival estimates were presented with Kaplan- Meier curves for allcause mortality and competing risk regression (cumulative incidence function with Fine- Gray method) for PE- related mortality. Variables used for adjustment were prespecified and included age (continuous), sex, sPESI, and history of diabetes mellitus, heart failure, prior ischemic stroke, and arterial vascular disease (either coronary or peripheral artery disease). In all models, those without history of AF were the reference group. For the assessment of the coprimary outcomes, because 90- day PE- related mortality rates are likely to affect 1- year mortality, we did not adjust the alpha level. However, it was planned to compare each of the patient subgroups with AF (ie, those with preexisting AF, as well as those with new incident AF) against those patients who did not have AF. Therefore, it was prespecified to set the significance level for the coprimary outcomes at P<0.025 (ie, reducing the alpha to half). All other comparisons were considered exploratory. RESULTS Of 92258 patients in RIETE, 48554 had PE. Based on the inclusion and exclusion criteria, 16497 patients with acute PE were included. Of those, 792 (4.8%) had known preexisting AF, whereas 445 (2.7%) were diagnosed with new incident AF within 48hours of the diagnosis of acute PE (Figure1). Baseline Characteristics and Presenting Features Patients with preexisting AF had differing baseline characteristics compared with those without AF. Patients with preexisting AF were older (77.9±0.4 versus 65.7±0.1 years), more likely to have diabetes mellitus (25.3% versus 15.9%), hypertension (77.0% versus 50.2%), and history of heart failure (33.8% versus 6.7%), (P<0.001 for pairwise all comparisons). The proportion of patients with hypotension (3.6% versus 3.0, P=0.29) or syncope (12.8% versus 14.1%, P=0.33) at presentation was comparable between those with preexisting AF and patients without AF. Patients with preexisting AF had higher CHA2DS2- VASC and sPESI scores compared with those without AF (P<0.001 for both comparisons [Table1]). Downloaded from http://ahajournals.org by on December 15, 2022 J Am Heart Assoc. 2021;10:e021467. DOI: 10.1161/JAHA.121.021467 4 Bikdeli et al Preexisting vs Incident AF in Patients With PE Patients with incident AF also had important differences in presenting features, compared with patients without AF. Comorbidities such as hypertension (63.9% versus 50.2%, P<0.001) and heart failure (10.8% versus 6.7%, P=0.001) were more frequently observed in patients with incident AF than those without AF. Further, patients with incident AF were more likely to present with hypotension (7.6% versus 3.0%, P<0.001) or syncope (18.0% versus 14.1%, P=0.02). As shown in Table1, patients with incident AF had higher CHA2DS2- VASC and sPESI scores compared with those without AF (P<0.001 for both comparisons). The gradient of risk according to the European Society of Cardiology classification is summarized in TableS1. Treatment Patterns Most patients in all 3 groups received initial anticoagulation. Use of percutaneous and surgical thrombectomy was rare (Table 2). Thrombolytic therapy was used in 1.1% of patients with preexisting AF, 4.3% of patients with incident AF, and 2.8% of patients without AF. At 1- year followup, a greater percentage of patients with preexisting AF were on anticoagulation than those who did not have a history of AF (75.2% versus 63.2%, P<0.001). Similarly, compared with those without AF, a greater proportion of patients with incident AF were on anticoagulation at 1- year followup (82.9% versus 63.2%, P<0.001). Outcomes at 90- Day Follow- Up All- Cause Mortality In unadjusted analyses, patients with preexisting AF had higher odds of 90- day mortality compared with those without AF (16.0% versus 6.1%; OR, 2.81; 95% CI, 2.33– 3.38). Findings were attenuated but consistent after multivariable adjustment (OR, 1.91; 95% CI, 1.57– 2.32). Patients with incident AF, compared with patients without AF, had higher odds of 90- day mortality in unadjusted analyses (13.0% versus 6.1%; OR, 2.28; 95% CI, 1.75– 2.97). Results were similar after multivariable adjustment (OR, 1.61; 95% CI, 1.23– 2.10) (Figure2A). Figure 1. Patient selection flow diagram. AF indicates atrial fibrillation; DVT, deep vein thrombosis; PE, pulmonary embolism; and RIETE, Registro Informatizado de Enfermedad Tromboembólica. Downloaded from http://ahajournals.org by on December 15, 2022 J Am Heart Assoc. 2021;10:e021467. DOI: 10.1161/JAHA.121.021467 5 Bikdeli et al Preexisting vs Incident AF in Patients With PE Thrombotic Outcomes Patients with preexisting AF had higher odds of 90- day PE- related mortality compared with those without AF (1.8% versus 0.76%; OR, 2.38; 95% CI, 1.37– 4.14, P=0.002). However, the results were not significant after multivariable adjustment (OR, 1.50; 95% CI, 0.85– 2.66). When compared with patients without AF, patients with incident AF had higher odds of 90- day PE- related mortality both in unadjusted (2.7% versus 0.76%; OR, Table 1. Cohort Characteristics of Patients With PE According to Presence and Time- Course of AF Known preexisting AF Incident AF (diagnosed within 2d after PE) No AF at all Number of patients (total N=16497) N=792 N=445 N=15260 Demographics Female sex, % 56.1% (99% CI, 51.4– 60.6) 52.8% (99% CI, 46.5– 58.9%) 51.3% (99% CI, 50.3– 52.3%) Age, y±SEM 77.9±0.4 75.2±0.6 65.7±0.1 Age, y, median±IQR 80 (72– 86) 78 (68– 84) 69 (55– 79) Prior history Current smoker 7.1% (99% CI, 4.9– 9.8%) 9.3% (99% CI, 6.0– 13.4%) 14.1% (99% CI, 13.4– 14.9%) Diabetes mellitus 25.3% (99% CI, 21.4– 29.5%) 18.1% (99% CI, 13.5– 23.2%) 15.9% (99% CI, 15.1– 16.7%) Hypertension 77.0% (99% CI, 72.9– 80.1%) 63.9% (99% CI, 57.7– 69.8%) 50.2% (99% CI, 4.9.1– 51.2%) Coronary artery disease 15.7% (99% CI, 12.5– 19.4%) 9.1% (99% CI, 6.0%– 13.3%) 6.7% (99% CI, 6.1– 7.2%) Peripheral arterial disease 8.5% (99% CI, 6.1– 114%) 4.2% (99% CI, 2.1– 7.3%) 3.5% (99% CI, 3.1– 3.9%) Coronary or peripheral arterial disease 22.0% (99% CI, 18.1– 26.1%) 12.5% (99% CI, 8.7– 17.1%) 9.4% (99% CI, 8.8– 10.0%) Heart failure 33.8% (99% CI, 29.6– 38.3%) 10.8% (99% CI, 7.3– 15.1%) 6.7% (99% CI, 6.1– 7.2%) Ischemic stroke 16.1% (99% CI, 12.9– 19.8%) 11.7% (99% CI, 8.1– 16.2%) 6.3% (99% CI, 5.8– 6.9) Prior (old) venous thromboembolism 13.4% (99% CI, 10.4– 16.8%) 9.0% (99% CI, 5.8– 13.0%) 14.1% (99% CI, 13.4– 14.8%) Coexisting deep vein thrombosis diagnosed with the index PE event 23.7% (99% CI, 19.9– 27.8%) 26.1% (99% CI, 20.1– 31.8%) 29.5% (99% CI, 28.6– 30.5%) Chronic lung disease 20.7% (99% CI, 17.1– 24.7%) 12.4% (99% CI, 8.7– 16.9%) 13.5% (99% CI, 12.8– 14.3%) Active cancer 17.3% (99% CI, 14.0– 21.0%) 16.9% (99% CI, 12.5– 21.9%) 16.7% (99% CI, 15.9– 17.5%) Anemia 39.3% (99% CI, 34.8– 43.9%) 33.0% (99% CI, 27.4– 39.1%) 30.9% (99% CI, 29.9– 31.9) Creatinine clearance levels, mL/min 73.3±247.3 66.4±31.5 87.1±64.3 Clinical factors Median (IQR) heart rate 90 (75– 110) 101 (85– 126) 90 (77– 103) Systolic blood pressure <90mmHg 3.6% (99% CI, 2.1– 5.7%) 7.6% (99% CI, 4.8– 11.5%) 3.0% (99% CI, 2.7– 3.4%) Syncope 12.8% (99% CI, 9.9– 16.2%) 18.0% (99% CI, 13.5– 23.1%) 14.1% (99% CI, 13.4– 14.8) Simplified Pulmonary Embolism Severity Index score, median±IQR 2 (1– 2) 1 (1– 2) 1 (0– 2) CHA2DS2VASC Score, median±IQR 4 (3– 5) 3 (2– 4) 2 (1– 4) Use of echocardiography within the first 3d of PE diagnosis 56.6 (99% CI, 51.7– 61.5%) 69.7% (99% CI, 63.7– 75.3%) 58.5% (99% CI, 57.4– 59.6%) Aspirin use at baseline 35.7% 26.2% 18.9% Categorical variables have been reported with their respective 99% CIs. Pairwise statistical comparisons were intentionally avoided to minimize type I error. AF indicates atrial fibrillation; IQR, interquartile range; and PE, pulmonary embolism. Downloaded from http://ahajournals.org by on December 15, 2022 J Am Heart Assoc. 2021;10:e021467. DOI: 10.1161/JAHA.121.021467 6 Bikdeli et al Preexisting vs Incident AF in Patients With PE 3.64; 95% CI, 2.01– 6.59, P<0.001) and multivariable adjusted analyses (OR, 2.29; 95% CI, 1.25– 4.18). (Figure2B). Bleeding Patients with preexisting AF had higher odds of 90- day major bleeding compared with those without AF (3.5% versus 2.0%; OR, 1.87; 95% CI, 1.27– 2.75). The association was no longer significant after multivariable adjustment (OR, 1.40; 95% CI, 0.93– 2.10). Similarly, patients with incident AF, compared with patients without AF, had higher odds of 90- day major bleeding (OR, 2.02; 95% CI, 1.24– 3.29), which was not significant after multivariable adjustment (OR, 1.48; 95% CI, 0.89– 2.45) (Figure2C). Outcomes at 1- Year Follow- Up All- Cause Mortality Patients with preexisting AF were at higher risk for 1- year allcause mortality compared with those without AF (HR, 2.62; 95% CI, 2.23– 3.07; P<0.001). Findings were attenuated but consistent after multivariable adjustment (HR, 1.77; 95% CI, 1.50– 2.10) (Figure3A). Patients with incident AF, compared with patients without AF, had higher risk of 1- year allcause mortality in unadjusted analyses (HR, 1.86; 95% CI, 1.46– 2.36; P<0.001). Results were attenuated but consistent in multivariable adjustment (HR, 1.34; 95% CI, 1.05– 1.71) (Figure3A and 3B). Thrombotic Outcomes Considering the competing risk of non- PE death, patients with preexisting AF had a higher risk of PE death at 1- year followup (HR, 2.27; 95% CI, 1.33– 3.86). However, the results were no longer significant after multivariable adjustment (HR, 1.50; 95% CI, 0.88– 2.60). Compared with those without AF, patients with incident AF had an increased hazard for 1- year PE- related mortality in analyses accounting for the competing Table 2. Treatment Patterns Known preexisting AF Incident AF (diagnosed within 2d after PE) No AF at all N=792 N=445 N=15260 Initial therapy Any anticoagulant therapy N=16440 N=787 N=444 N=15209 Lowmolecular- weight heparin 676 (86%) 397 (89%) 12696 (83%) Unfractionated heparin 42 (5.3%) 18 (4.1%) 879 (5.8%) Fondaparinux 14 (1.8%) 2 (0.45%) 227 (1.5%) Direct oral anticoagulants 23 (2.9%) 4 (0.90%) 902 (5.9%) Thrombolytic therapy 9 (1.1%) 19 (4.3%) 420 (2.8%) Surgical or percutaneous thrombectomy N=14762 N=674 4 (0.59%) N=400 3 (0.75%) N=13688 169 (1.2%) Vena cava filter use 18 (2.3%) 20 (4.5%) 377 (2.5%) No anticoagulant therapy 2 (0.25%) 1 (0.22%) 16 (0.10%) Longterm treatment (among survivors with valid followup information) Vitamin K antagonists 274 (35%) 201 (45%) 6942 (47%) Lowmolecular- weight heparin 235 (30%) 128 (29%) 4214 (28%) Direct oral anticoagulants 210 (27%) 83 (19%) 3504 (24%) Fondaparinux 4 (0.51%) 3 (0.67%) 78 (0.53%) Unfractionated heparin 4 (0.51%) 032 (0.22%) Others 5 (0.63%) 2 (0.45%) 30 (0.20%) Anticoagulation at 90d Patients alive and followed 664 386 14306 Patients alive and still on anticoagulation 620 (93.4%) 372 (96.4%) 13801 (96.5%) Anticoagulation at 180d Patients alive and followed 434 252 9250 Patients alive and still on anticoagulation 369 (85.0%) 226 (89.7%) 7941 (85.8%) Anticoagulation at 365d Patients alive and followed 258 164 5607 Patients alive and still on anticoagulation 194 (75.2%) 136 (82.9%) 3541 (63.2%) AF indicates atrial fibrillation; and PE, pulmonary embolism. Downloaded from http://ahajournals.org by on December 15, 2022 J Am Heart Assoc. 2021;10:e021467. DOI: 10.1161/JAHA.121.021467 7 Bikdeli et al Preexisting vs Incident AF in Patients With PE risk of non- PE death (HR, 3.24; 95% CI, 1.80– 5.85). Findings persisted after multivariable adjustment (HR, 2.18; 95% CI, 1.18– 4.04) (Figure4B). Accounting for the competing risk of nonthrombotic death, patients with preexisting AF had a nonsignificant increase in the risk of recurrent VTE (HR, 1.54; 95% CI, 0.96– 2.45) and a 5- fold increased risk of stroke (HR, 5.48; 95% CI, 3.10– 9.69) (Figure4C). Patients with preexisting AF had a higher risk of the composite thrombotic outcome compared with those who did not have AF, both in unadjusted analyses (HR, 2.31; 95% CI, 1.63– 3.26) as well as in multivariable adjusted analyses (HR, 1.86; 95% CI, 1.29– 2.70, Figure 4E). Among patients with PE and incident AF, the composite thrombotic outcome was rare at 1- year follow up, with only 6 thrombotic events, including 5 recurrent nonfatal VTEs but no ischemic strokes. As such, in models accounting for nonthrombotic death as the competing risk, patients with incident AF— compared with patients without AF— did not have an increased risk for recurrent VTE (HR, 0.68; 95% CI, 0.27– 1.65) or the composite thrombotic outcome (HR, 0.61; 95% Figure 2. Ninetyday clinical outcomes based on presence of preexisting or incident AF. Patients with no AF were the reference group in all analyses. *Adjusted for age, sex, simplified Pulmonary Embolism Severity Index, and history of diabetes mellitus, heart failure, prior ischemic stroke, and arterial vascular disease (either coronary or peripheral artery disease). AF indicates atrial fibrillation; and PE, pulmonary embolism. Downloaded from http://ahajournals.org by on December 15, 2022 J Am Heart Assoc. 2021;10:e021467. DOI: 10.1161/JAHA.121.021467 8 Bikdeli et al Preexisting vs Incident AF in Patients With PE CI, 0.27– 1.38) (Figure 4E). Given the paucity of events, multivariable analysis was not performed. Bleeding Patients with preexisting AF had increased 1- year risk of major bleeding in unadjusted analyses compared with those without AF (Fine- Gray HR, 1.60; 95% CI, 1.13– 2.27), but the findings were no longer significant after multivariable adjustment (HR, 1.16; 95% CI, 0.79– 1.67). Compared with patients without AF, patients with incident AF had increased unadjusted 1- year risk of major bleeding accounting for the competing risk of nonhemorrhagic death (HR, 1.65; 95% CI, 1.05– 2.58). The results were no longer significant after multivariable adjustment. Sensitivity Analysis Owing to clinicians’ discretionary decisions for hospital discharge, inhospital outcomes were not prespecified for the main analyses. Sensitivity analyses showed that inhospital outcomes were broadly similar to 30- day results (data not shown). DISCUSSION Among patients with acute symptomatic PE, both preexisting and newly incident AF were associated with greater frequency of cardiovascular risk factors, and higher CHA2DS2VASC and sPESI scores, compared with patients without AF. Both forms of AF were associated with adverse outcomes, including allcause mortality, although the pattern of risk had distinct features based on the timing of AF onset. Preexisting AF was associated with increased risk of subsequent thrombotic events, including stroke, but not a significantly increased risk for PE- related mortality, once adjusted for sPESI and comorbid conditions. In contrast, incident AF was associated with increased risk of PE- related mortality but not with longterm risk of stroke or the composite thrombosis end point. Although some findings were partially attributable to underlying risk factors, others persisted even in multivariable adjusted analyses. Findings from this study add novel information to complement prior studies about concomitant AF in patients with PE. The proportion of patients with preexisting AF and incident AF reported in this study are in range with prior reports.15,19 Some prior studies,26,27 including a metaanalysis,28 indicated an increased Figure 3. Kaplan Meier curve for allcause death (A) and competing risk regression (Fine and Grey) for PE- related death (B). AF indicates atrial fibrillation; and PE, pulmonary embolism. Figure 4. Oneyear outcomes based on presence of preexisting or incident AF. Patients with no AF were the reference group in all analyses. (A) allcause mortality ((B)) PE- related mortality, (C) ischemic stroke, (D) recurrent VTE (E) composite thrombotic outcome. In all models other than allcause mortality, competing risk of death was considered; see text for details. In models where the number of events were very few, multivariable adjustment was not pursued. *Adjusted for age, sex, simplified Pulmonary Embolism Severity Index, and history of diabetes mellitus, heart failure, prior ischemic stroke, and arterial vascular disease (either coronary or peripheral artery disease). †No patient with incident AF developed ischemic stroke during followup. AF indicates atrial fibrillation; PE, pulmonary embolism; and VTE, venous thromboembolism. Downloaded from http://ahajournals.org by on December 15, 2022 J Am Heart Assoc. 2021;10:e021467. DOI: 10.1161/JAHA.121.021467 9 Bikdeli et al Preexisting vs Incident AF in Patients With PE risk for shock and mortality in patients with PE who had coexisting AF, whereas others did not show a significant association.19,29 Our investigation, based on a large patient population showed a clinically meaningful and statistically significant association between AF and clinical outcomes. Further, we were able to conduct multivariable analyses, without concern for small number of events. Downloaded from http://ahajournals.org by on December 15, 2022