Direct oral anticoagulants (DOACs) are effective for stroke prevention in nonvalvular atrial fibrillation (AF). Cardioversion (CV) is frequently performed in patients with AF or flutter. To further explore the safety profile of DOACs in the context of CV, we sought to assess the prevalence of intracardiac thrombi under DOAC therapy in comparison with treatment with vitamin K antagonists. A total of 672 transesophageal echocardiograms performed in 643 patients with a history of nonvalvular AF were analyzed. The median CHA 2 DS 2 -VASc score was 4. Cases were stratified according to anticoagulation with dabigatran (n = 79), rivaroxaban (n = 122), phenprocoumon (n = 180), or bridging therapy (n = 287). In a subgroup analysis, only patients receiving phenprocoumon with an international normalized ratio ≥2 on the day of the investigation or on DOAC therapy for ≥3 weeks were considered. The prevalence of intracardiac thrombi under phenprocoumon was significantly higher than under DOACs (phenprocoumon, 17.8%; all DOACs, 3.9%; dabigatran, 3.8%; rivaroxaban, 4.1%) and showed no significant difference to bridging therapy (12.5%). In patients with sufficient short-term anticoagulation, similar differences between DOAC and phenprocoumon groups were observed (phenprocoumon, 18.4%; all DOACs, 3.8%; dabigatran, 0%; rivaroxaban, 6.6%). The influence of anticoagulation medication on thrombus rates was confirmed after adjusting for baseline intergroup differences regarding left atrial size and CHA 2 DS 2 -VASc score. In conclusion, the prevalence of intracardiac thrombi was lower under DOAC therapy than under phenprocoumon in this high-risk patient cohort. Safety of CV during DOAC treatment requires further prospective evaluation.
Electrical or pharmacologic cardioversion (CV) is commonly applied to restore sinus rhythm in patients with atrial fibrillation (AF) or flutter. However, CV is associated with a significant periprocedural thromboembolic risk that is attributed to thrombus mobilization or atrial “stunning” after conversion to sinus rhythm. An individual risk for thromboembolic events of up to 9.8% has been reported that may be reduced to 0.5% to 0.8% by sufficient periprocedural anticoagulation. Therefore, in patients with AF lasting for >48 hours, current guidelines recommend either exclusion of intracardiac thrombi by transesophageal echocardiography (TEE) or therapeutic oral anticoagulation with vitamin K antagonists (VKAs) for ≥3 weeks before CV. Direct oral anticoagulants (DOACs, non-VKA) have shown similar or superior efficacy and safety in comparison with VKAs in nonvalvular AF. However, there are still underexplored aspects related to the management of patients on DOACs. Specifically, data regarding the safety of CV during DOAC therapy are limited. Given the increasing use of DOACs in clinical practice, it is crucial to further elucidate the thromboembolic risk associated with CV under these agents. Therefore, the aim of this study was to assess the prevalence of intracardiac thrombi in patients with AF who are treated with DOACs compared with patients receiving VKAs.
Methods
The study was conducted in compliance to the Declaration of Helsinki, and the research protocol was approved by the Ethics Committee of Heidelberg University (Germany; approval number S-458-2013). Written informed patient consent was not required for this study according to the Ethics Committee. The prevalence of intracardiac thrombi was assessed in patients with a history of AF who underwent TEE at the Department of Cardiology of Heidelberg University (Germany) from January 01, 2012, to January 20, 2014. A total of 2,911 transesophageal echocardiograms were screened, and investigations conducted during treatment with oral anticoagulants or bridging therapy at the time of the examination were selected for further analysis. Patients exhibiting mitral valve stenosis or rheumatic valve disease, subjects carrying mechanical heart valves, and repeated examinations on 1 patient under the same anticoagulant therapy were excluded. A total of 672 cases met the selection criteria and were divided into 4 groups according to anticoagulation therapy: phenprocoumon, rivaroxaban, dabigatran, and bridging therapy with low–molecular weight heparin or unfractionated heparin. Four patients received apixaban for oral anticoagulation. Because of the small number, these are not presented as an individual group. However, for completeness, the data were included in pooled DOAC analyses.
The primary study end point was the presence of an intracardiac thrombus. In addition, the detection of spontaneous echo contrast (SC) was assessed. The prevalence of intracardiac thrombi in the phenprocoumon group was compared with thrombus rates in patients on DOAC treatment or bridging and to a pooled group of all transesophageal echocardiograms recorded under DOACs. In a second step, a subgroup analysis of patients under phenprocoumon with an international normalized ratio (INR) ≥2 on the day of the TEE or under DOAC therapy for ≥3 weeks without documented treatment interruption until <24 hours before TEE was carried out. Echocardiographic findings and parameters were obtained from written TEE reports of study patients. Left atrial size was included from previously (<6 months) recorded TEE or transthoracic echocardiographic examinations if the value was not provided in the index report. Demographic data, anticoagulation therapy, and concomitant diseases were derived from the patients’ files. Risk factors for thromboembolic events (CHA 2 DS 2 -VASc score) or bleeding (HAS-BLED score) were assessed in accordance with current guidelines.
Statistical analysis was performed using SPSS (version 22; IBM, Armonk, New York) and SAS (version 9.3; SAS Institute, Cary, North Carolina) software. Continuous variables were described as median and 25th and 75th percentiles, and the Kruskal-Willis test was applied for between-group comparisons. Categorical data are presented as frequency and percentage and were compared using the chi-square test. Logistic regression was applied to adjust for intergroup differences in baseline parameters CHA 2 DS 2 -VASc score and left atrial size. Whenever computationally feasible, exact inference was applied to take into account sparseness of data, otherwise asymptotic logistic regression methods were applied.
Results
A total of 643 patients with AF (n = 590) or atrial flutter (n = 53) were included. The median patient age was 72 years, the median CHA 2 DS 2 -VASc score was 4, and 100 patients (15.6%) had a history of stroke, transient ischemic attack, or systemic thromboembolism (TE; Table 1 ). Sixty-eight patients (10.6%) exhibited at least 1 intracardiac thrombus. Thrombi were predominantly detected in the left atrial appendage (LAA) or the left atrium (LA) (n = 49; 72.1%), whereas 19 patients (27.9%) showed thrombi on pacemaker (PM) or implantable cardioverter defibrillator (ICD) leads, 3 (4.4%) in the right atrium and 1 (1.5%) in the left ventricle ( Figure 1 ). Four patients had thrombus formation at 2 locations. Patients developing intracardiac thombi were primarily characterized by chronic forms of AF (i.e., persistent and permanent AF) and displayed higher CHA 2 DS 2 -VASc scores, more severe left atrial dilation, thrombogenic flow velocities in the LA/LAA, and functional impairment of the left ventricle ( Table 1 ). In addition, the presence of PM or ICD, co-medication with aspirin, and a history of vascular disease were more common in patients with thrombi ( Table 1 ).
| Intracardiac thrombus (n = 68) | No thrombus (n = 575) | p Value | |
|---|---|---|---|
| Age (years) | 72.0 [62.5; 78.0] | 71.0 [63.0; 77.0] | 0.564 |
| Male | 46 (68%) | 375 (65%) | 0.690 |
| Body mass index (kg/m 2 ) | 26.2 [24.3; 29.8] (n = 66) | 27.1 [24.0; 30.3] (n = 567) | 0.319 |
| CHA 2 DS 2 -VASc | 4.0 [3.0; 5.0] | 4.0 [2.0; 5.0] | 0.002 |
| 0-1 | 2 (3%) | 66 (12%) | |
| 2-3 | 17 (25%) | 197 (34%) | |
| 4-5 | 33 (49%) | 231 (40%) | |
| 6-7 | 14 (21%) | 75 (13%) | |
| 8-9 | 2 (3%) | 6 (1%) | |
| HAS-BLED | 1.0 [1.0; 2.0] | 1.0 [1.0; 2.0] | 0.264 |
| 0 | 11 (16%) | 129 (22%) | |
| 1 | 34 (50%) | 274 (48%) | |
| 2 | 16 (24%) | 125 (22%) | |
| 3 | 6 (9%) | 39 (7%) | |
| 4 | 1 (2%) | 7 (1%) | |
| 5-6 | 0 | 1 (0%) | |
| Left atrium size (mm) | 49.0 [45.0; 54.0] (n = 58) | 46.0 [42.0; 50.0] (n = 507) | 0.002 |
| Reduced left atrial flow velocity | 33 (49%) | 95 (17%) | <0.001 |
| Coronary artery disease | 52 (77%) | 388 (68%) | 0.131 |
| Aspirin | 14 (21%) | 44 (8%) | <0.001 |
| Aspirin and clopidogrel | 2 (3%) | 19 (3%) | 0.873 |
| Left ventricular ejection fraction (%) | <0.001 | ||
| >55 | 13 (20%) | 292 (51%) | |
| 45-54 | 9 (14%) | 98 (17%) | |
| 30-44 | 14 (22%) | 80 (14%) | |
| <30 | 29 (45%) | 100 (18%) | |
| Data not available | 3 | 5 | |
| Rhythm status | 0.002 | ||
| Paroxysmal AF | 13 (24%) | 197 (42%) | |
| Persistent AF | 17 (31%) | 136 (29%) | |
| Permanent AF | 22 (40%) | 91 (19%) | |
| Atrial flutter | 3 (6%) | 50 (11%) | |
| Data not available | 13 | 101 | |
| Pacemaker or ICD | 39 (57%) | 119 (21%) | <0.001 |
| Diabetes | 18 (27%) | 122 (21%) | 0.321 |
| Hypertension | 62 (91%) | 506 (88%) | 0.440 |
| Stroke, TIA, or TE | 15 (22%) | 85 (15%) | 0.117 |
| Vascular disease | 45 (66%) | 298 (52%) | 0.025 |
Among 672 TEE examinations performed in study patients, VKAs (phenprocoumon) were used for anticoagulation in 180 cases (26.8%; Table 2 ). Two hundred five patients (30.5%) received DOAC therapy (dabigatran, n = 79, 11.8%; rivaroxaban, n = 122, 18.2%). Additional 287 TEE investigations (42.7%) were carried out under bridging therapy with low–molecular weight heparin or unfractionated heparin. In the dabigatran group, most patients received 150 mg twice a day (n = 43, 54.4%) or 110 mg twice a day (n = 35, 44.3%), whereas 1 patient (1.3%) was treated with 75 mg twice a day. Rivaroxaban was administered as 20, 15, or 10 mg everyday in 100 (82.0%), 19 (15.6%), and 3 cases (2.5%), respectively. Statistically significant baseline differences between treatment groups were observed regarding several parameters. Patients under DOACs were younger, more often male, had lower CHA 2 DS 2 -VASc score and left atrial size, lower prevalence of coronary artery disease, higher left ventricular ejection fraction, and lower rates of permanent AF ( Table 2 ). They also less often carried a PM or ICD.
| Phenprocoumon (n = 180) | Dabigatran (n = 79) | Rivaroxaban (n = 122) | Bridging (n = 287) | p Value | |
|---|---|---|---|---|---|
| Age (years) | 73.0 [64.0; 78.0] | 68.0 [59.0; 74.0] | 70.0 [60.0; 75.0] | 72.0 [64.0; 78.0] | 0.002 |
| Male | 100 (56%) | 54 (68%) | 83 (68%) | 199 (69%) | 0.01 |
| Body mass index (kg/m 2 ) | 26.8 [24.4; 30.0] (n = 178) | 27.2 [23.7; 30.3] (n = 78) | 26.8 [23.4; 29.7] (n = 121) | 26.9 [24.0; 30.2] (n = 281) | 0.663 |
| CHA 2 DS 2 VASc | 4.0 [3.0; 5.0] | 3.0 [2.0; 4.0] | 3.0 [2.0; 5.0] | 4.0 [3.0; 5.0] | <0.001 |
| 0-1 | 11 (6%) | 14 (18%) | 25 (21%) | 19 (7%) | |
| 2-3 | 54 (30%) | 35 (44%) | 43 (35%) | 90 (31%) | |
| 4-5 | 83 (46%) | 21 (27%) | 38 (31%) | 133 (46%) | |
| 6-7 | 30 (17%) | 9 (11%) | 16 (13%) | 40 (14%) | |
| 8-9 | 2 (1%) | 0 | 0 | 5 (2%) | |
| HAS-BLED | 1.0 [1.0; 2.0] | 1.0 [0.0; 2.0] | 1.0 [0.0; 2.0] | 1.0 [1.0; 2.0] | 0.008 |
| 0 | 32 (18%) | 27 (34%) | 39 (32%) | 48 (17%) | |
| 1 | 89 (49%) | 32 (41%) | 51 (42%) | 146 (51%) | |
| 2 | 47 (26%) | 12 (15%) | 27 (22%) | 63 (22%) | |
| 3 | 10 (6%) | 6 (8%) | 5 (4%) | 25 (9%) | |
| 4 | 2 (1%) | 2 (3%) | 0 | 4 (1%) | |
| 5-6 | 0 | 0 | 0 | 1 (0%) | |
| Left atrial size (mm) | 47.0 [44.0; 53.0] (n = 156) | 45.0 [42.0; 49.0] (n = 67) | 44.0 [40.0; 48.0] (n = 109) | 47.0 [43.0; 52.0] (n = 256) | 0.002 |
| Reduced left atrial flow velocity | 49 (27%) | 14 (18%) | 19 (16%) | 55 (19%) | 0.073 |
| Coronary artery disease | 127 (71%) | 49 (62%) | 67 (55%) | 219 (76%) | <0.001 |
| Aspirin | 16 (9%) | 7 (9%) | 9 (7%) | 27 (9%) | 0.934 |
| Aspirin and clopidogrel | 2 (1%) | 4 (5%) | 2 (2%) | 14 (5%) | 0.138 |
| Left ventricular ejection fraction (%) | <0.001 | ||||
| >55 | 78 (44%) | 40 (51%) | 77 (63%) | 117 (42%) | |
| 45-54 | 35 (20%) | 13 (17%) | 23 (19%) | 41 (15%) | |
| 30-44 | 29 (16%) | 4 (5%) | 16 (13%) | 50 (18%) | |
| <30 | 35 (20%) | 21 (27%) | 6 (5%) | 73 (26%) | |
| Data not available | 3 | 1 | 0 | 6 | |
| Rhythm status | <0.001 | ||||
| Paroxysmal AF | 49 (36%) | 26 (39%) | 43 (43%) | 96 (39%) | |
| Persistent AF | 39 (28%) | 28 (42%) | 33 (33%) | 66 (27%) | |
| Permanent AF | 37 (27%) | 6 (9%) | 5 (5%) | 68 (28%) | |
| Atrial flutter | 13 (9%) | 7 (10%) | 18 (18%) | 14 (6%) | |
| Data not available | 42 | 12 | 23 | 43 | |
| Pacemaker or ICD | 57 (32%) | 15 (19%) | 11 (9%) | 89 (31%) | <0.001 |
| Diabetes | 40 (22%) | 12 (15%) | 19 (16%) | 75 (26%) | 0.092 |
| Hypertension | 164 (91%) | 69 (87%) | 100 (82%) | 259 (90%) | 0.096 |
| Stroke, TIA, or TE | 28 (16%) | 10 (13%) | 18 (15%) | 49 (17%) | 0.861 |
| Vascular disease | 101 (56%) | 31 (39%) | 60 (49%) | 164 (57%) | 0.055 |
The highest thrombus rate was observed in patients on VKA therapy with phenprocoumon (17.8%; Table 3 , Figure 2 ). In patients receiving DOACs for anticoagulation, the prevalence of intracardiac thrombi was significantly lower (3.9%). This finding was confirmed when thrombus rates under dabigatran (3.8%) or rivaroxaban (4.1%) were individually compared with phenprocoumon ( Table 3 , Figure 2 ). Most thrombi (n = 2 of 3) in the dabigatran group occurred in patients receiving 110 mg twice a day, whereas all thrombi (5 of 5) in the rivaroxaban group were seen under 20 mg everyday. In addition, there was a tendency toward reduced thrombus rates under bridging therapy (12.5%) compared with phenprocoumon that did not reach statistical significance ( Table 3 , Figure 2 ). The influence of anticoagulation on thrombus rates under VKA therapy versus DOAC treatment was confirmed after applying logistic regression to adjust for group differences in CHA 2 DS 2 -VASc score and left atrial size (phenprocoumon vs all DOACs, p = 0.0005; phenprocoumon vs dabigatran, p = 0.007; phenprocoumon vs rivaroxaban, p = 0.005; phenprocoumon vs bridging, p = 0.20). Of note, analogous differences regarding thrombus rates between treatment groups were detected when the analysis was restricted to thrombi located in the LA and LAA (phenprocoumon, 13.5%; DOAC, 2.5%; dabigatran, 2.6%; rivaroxaban, 2.5%; bridging, 9.7%; Table 4 ).
