Open Access

Incidence of left atrial abnormalities under treatment with dabigatran, rivaroxaban, and vitamin K antagonists

  • Stefan Reers1Email author,
  • Tolga Agdirlioglu2,
  • Michael Kellner2,
  • Matthias Borowski3,
  • Holger Thiele2,
  • Johannes Waltenberger1 and
  • Michael Reppel2
Contributed equally
European Journal of Medical Research201621:41

https://doi.org/10.1186/s40001-016-0235-8

Received: 22 March 2016

Accepted: 10 October 2016

Published: 21 October 2016

Abstract

Background

Non-vitamin K antagonist oral anticoagulants (NOACs) such as dabigatran or rivaroxaban are alternatives to vitamin K antagonists (VKAs) for prevention of stroke and systemic embolism in patients with atrial fibrillation (AF) and atrial flutter (AFL). Incidences of risk factors for left atrium (LA) and left atrial appendage (LAA) thrombus formation, such as dense spontaneous echo contrast (SEC), low LAA velocity (LAAV) <20 cm/s under treatment with dabigatran and rivaroxaban in comparison with VKAs are unknown.

Methods

We studied 306 patients with AF (94 %) and AFL (6 %) undergoing transesophageal echocardiography. Patients received VKAs (n = 138), dabigatran (n = 68), or rivaroxaban (n = 100) for at least 3 weeks prior to investigation. Time in therapeutic range was 67 % for VKA. Mean CHADS2 score and CHA2DS2-VASc score were 1.3 and 2.5, respectively. Left atrial abnormality was defined as either dense SEC, low LAAV <20 cm/s, or thrombus.

Results

Any LA abnormality occurred in 9, 3, and 5 % of patients receiving VKA, dabigatran, and rivaroxaban, respectively. The most frequent abnormality was LAA thrombus (VKA: 4 %, dabigatran: 0 %, rivaroxaban: 2 %) and low LAAV of less than 20 cm/s (VKA: 4 %, dabigatran: 1 %, rivaroxaban: 1 %), followed by dense SEC (VKA: 2 %, dabigatran: 1 %, rivaroxaban: 2 %). Results of uni- and multivariate analyses revealed a numerically lower but not significantly different frequency of any LA abnormality under dabigatran (OR 0.4, 95 % Cl 0.08 − 1.88, p = 0.25) and rivaroxaban (OR 0.65, 95 % Cl 0.22 − 1.98, p = 0.45) compared to VKA.

Conclusion

With respect to the incidence of LA abnormalities, dabigatran and rivaroxaban are not inferior to VKA.

Keywords

Vitamin K antagonist Dabigatran Rivaroxaban Thrombus Atrial fibrillation Left atrial appendage

Background

Non-valvular atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, and is associated not only with an increased risk of stroke and other systemic embolism but also increased mortality and morbidity [14]. In comparison to the general population, the risk of stroke is four- to fivefold higher in patients with AF [5]. An overview of five randomized trials has shown that treatment with vitamin K antagonists (VKA) reduced the incidence of ischemic stroke from 4.5 to 1.4 %/year with a relative risk reduction of 68 % in AF patients [6]. Pharmacokinetics and pharmacodynamics of VKA are influenced by many factors including nutrition leading to fluctuant international normalized ratio (INR) values and individual changes of the time in therapeutic range (TTR). Non-vitamin K antagonist oral anticoagulants (NOACs), including the direct thrombin inhibitor dabigatran and the factor Xa inhibitors rivaroxaban, revealed a clinical benefit compared with VKA in large-scale phase III studies [7, 8]. Despite these benefits, there are many open questions in terms of specific clinical situations. Based on guidelines, for patients with AF of >48 h duration, therapeutic anticoagulation is recommended for at least 3 weeks prior to and 4 weeks after cardioversion to exclude left atrial appendage (LAA) thrombus [9, 10]. While the efficacy of VKAs for prevention of stroke and systemic embolism in the cardioversion setting has been studied in detail [11, 12], only few studies have been published for NOACs [1315]. A recently published study compared NOACs and VKAs in a high-risk population, i.e., patients with a median CHA2DS2-VASc score of 4. The prevalence of intracardiac thrombi under VKAs was unexpectedly high (17.8 %) bearing risk of thromboembolic events despite sufficient anticoagulation. However, it was significantly higher than under dabigatran (3.8 %) or rivaroxaban (4.1 %). The TTR of VKA patients in that study is not known. The authors concluded that the prevalence of intracardiac thrombi was lower under NOAC therapy than under VKAs [16].

Potential risk factors for thrombus formation in LA/LAA, such as dense spontaneous echo contrast (SEC), and low left atrial appendage velocity (LAAV <20 cm/s) that are known as independent risk factors for thromboembolic events have not been studied yet in detail [1719]. It has been demonstrated that these transesophageal echocardiogram (TEE) findings were stronger predictors of thromboembolic events than the CHADS2 score [20] and that the annual rate of cerebral embolism was 22 %, despite oral anticoagulation [21]. Although VKAs seem to be similarly effective than NOACs, the incidences of these echocardiographic LA abnormalities under treatment with dabigatran, rivaroxaban, and VKAs especially in a mid- or low-risk population are unknown. Therefore, the aim of the present registry study was to identify the frequencies of LA abnormalities in patients treated with VKAs at a sufficient TTR of at least 65 %, dabigatran or rivaroxaban.

Methods

Study population

We studied 306 patients with AF and atrial flutter (AFL) under treatment with VKAs, dabigatran, or rivaroxaban referred to our department for cardioversion or catheter ablation between October 2011 and December 2014. Exclusion criteria were atrial fibrillation due to a reversible cause (e.g., hyperthyroidism, infection, transient perioperative AF), moderate or severe heart-valve disorder or prosthetic heart valve, heart transplant, need for aspirin at a dose of >100 mg/day or for both aspirin and a P2Y12 inhibitor, active liver disease, calculated creatinine clearance of <15 ml per minute, pregnancy, stroke within 14 days prior to admission, and non-compliance with drug therapy.

All included patients with creatinine clearance ≥50 ml/min and HAS-BLED score <3 in the dabigatran and rivaroxaban group received the standard dose of 150 mg BID and 20 mg OD, respectively. Only patients with moderate renal impairment (creatinine clearance 30–49 ml/min) or high bleeding risk (HAS-BLED score ≥3) were treated with reduced dose of 110 mg BID dabigatran or 15 mg OD rivaroxaban, as recommended in the European Society of Cardiology (ESC) guidelines for the management of AF [9].

Scores

The risk of stroke or systemic embolism and hemorrhage was determined using the CHADS2, CHA2DS2-VASc, and HAS-BLED scores [9].

Transthoracic (TTE) and transesophageal echocardiography (TEE)

All included patients were studied by TEE and optionally TTE (Vivid E9, GE Healthcare, USA). Echocardiographic measurements were performed according to the recommendations of the international standard practice guidelines [22, 23]. TTE was performed using a 1.5–4.6 MHz imaging transducer (M5S-D and M5Sc-D, GE Healthcare, USA). For TEE 3.0–8.0 MHz, a multiplane phased array transducer (6VT-D, GE Heathcare, USA) was used. Patients were sedated with midazolam and/or propofol. Blood pressure, heart rate, and oxygen saturation were continuously monitored. LA and LAA were studied in multiple planes. LAAs were categorized into non-banded and banded LAAs and four different morphology subgroups, as first described by Wang et al. [24]: chicken wing, wind sock, cauliflower, and cactus.

LA abnormality

LA abnormality was defined as thrombus in LA/LAA, dense SEC, and severely reduced LAAV (≤20 cm/s) [17, 19]. We constituted a rank order: patients with proof of LA/LAA thrombus were not included in the dense SEC- or LAAV <20 cm/s group and patients with dense SEC were not included in the LAAV <20 cm/s group.

Thrombus was defined as an iso- or hyperechogenic non-muscular and non-endocardial mass detected by more than one plane axis [25]. LAAV was measured by pulsed-wave (PW) Doppler as maximal flow velocity in the proximal third of the appendage. The view with the optimal alignment was determined by color flow imaging [26]. The density of SEC was graded in 5 levels, as described before [26]: (0) absence of echogenicity, (+1) mild (minimal echogenicity located only in a part of the LA cavity, only transiently during the cardiac cycle, and only at high gain setting), (+2) mild to moderate (denser swirling than mild SEC but only demonstrable at high gain setting), (+3) moderate (dense swirling in the LAA und partially in the LA cavity with varying intensity), (+4) dense (intense echodensity and very slow swirling in LAA).

To calculate the time in therapeutic range (TTR) for VKA group patients, the Rosendaal method was used [27]. The INR values of the last 6 weeks were included in the calculation.

Statistical analysis

The study population was described by the standard descriptive statistics such as frequencies, mean ± standard deviation, median with the corresponding interquartile range, wherever appropriate. Inferential statistics were intended to be exploratory (hypotheses generating), not confirmatory, and are interpreted accordingly. Thus, p values are to be interpreted in Fisher’s sense, representing the metric weight of evidence against the respective null hypothesis. Neither a global significance level nor local levels were determined. A p value ≤0.05 was considered statistically significant.

Pair-wise differences between the anticoagulation groups (VKA vs. dabigatran, VKA vs. rivaroxaban, and dabigatran vs. rivaroxaban) were assessed respectively using Fisher’s exact test (for categorical variables with two categories), the Chi2-test (for categorical variables with three or more categories), and the Mann–Whitney-U-test (for continuous variables).

In order to prevent biased results due to imbalanced patient’s baseline characteristics, the impact of anticoagulation on the risk of any LA/LAA abnormality was assessed by multivariate logistic regression. Model building was carried out by means of all-subset variable selection based on Akaike’s information criterion [28]. Coefficients from logistic regression were checked by the Wald-test, and odds ratios (OR) and referring 95 % confidence intervals (CI) were derived. All statistical computations were carried out using R 3.1.2 (R Core Team, 2014).

Results

Baseline characteristics

Table 1 shows the clinical baseline characteristics of the 306 patients included. The mean age was 67 with an interquartile range of 58–73, 60 % were male. Most of the patients had paroxysmal AF (56 %), followed by persistent AF (36 %), permanent (1 %), and longstanding persistent (<1 %). 6 % were suffering from AFL. In the VKA group, the TTR, defined as an INR between 2.0 to 3.0, was 67 %. Between the three treatment groups, some significant differences were observed (for more details see Table 1).
Table 1

Baseline characteristics of the study population

Variable

Dabigatran, N = 68 (22 %)

VKA, N = 138 (45 %)

Rivaroxaban, N = 100 (33 %)

p value for difference between VKA and dabigatran

p value for difference between VKA and rivaroxaban

p value for difference between dabigatran and rivaroxaban

Age: year

 Median

66

68.5

64

0.16

0.052

0.738

 Interquartile range

58–72

60–74

55.8–72

   

Male sex: no. (%)

48 (71 %)

78 (57 %)

57 (57 %)

0.068

1

0.078

Body–mass index

 Median

27.2

27.5

28.4

0.809

0.196

0.209

 Interquartile range

24.9–31.4

25.0–30.9

25.5–32.9

   

 Hypertension

43 (63 %)

102 (74 %)

69 (69 %)

0.119

0.562

0.266

 Diabetes mellitus

14 (21 %)

32 (23 %)

18 (18 %)

1

0.266

0.279

LA size: cm2

 Median

4.1

4

4.1

0.122

0.846

0.216

 Interquartile range

3.6–4.5

3.4–4.3

3.1–4.4

   

 LA size ≥ 5.5 cm2: no. (%)

2 (3 %)

3 (2 %)

2 (2 %)

1

1

1

LVEF classification: no. (%)

 Normal (≥55 %)

55 (81 %)

119 (86 %)

77 (77 %)

0.567

0.328

0.652

 Mildly reduced (45–54 %)

7 (10 %)

11 (8 %)

14 (14 %)

   

 Moderately reduced (30–44 %)

4 (6 %)

7 (5 %)

8 (8 %)

   

 Severely reduced (<30 %)

2 (3 %)

1 (1 %)

1 (1 %)

   

Renal function; creatinine clearance; classification—no. (%)

 Normal (>80 ml/min)

57 (84 %)

102 (74 %)

74 (74 %)

0.247

0.973

0.266

 Mild impairment (51–80 ml/min)

11 (16 %)

35 (25 %)

25 (25 %)

   

 Moderate impairment (31–50 ml/min)

0 (0 %)

1 (1 %)

1 (1 %)

   

 Severe impairment (≤30 ml/min)

0 (0 %)

0 (0 %)

0 (0 %)

   

Classification of atrial fibrillation—no. (%)

 Paroxysmal

44 (65 %)

81 (59 %)

47 (47 %)

0.792

0.054

0.097

 Persistent

20 (29 %)

49 (36 %)

42 (42 %)

   

 Longstanding persistent

0 (0 %)

1 (1 %)

1 (1 %)

   

 Permanent

1 (1 %)

3 (2 %)

0 (0 %)

   

 Atrial flutter

3 (4 %)

4 (3 %)

10 (10 %)

   

CHADS2

 Mean score (±SD)

1.1 (±0.8)

1.5 (±0.9)

1.2 (±0.8)

0.003

0.006

0.521

 Score—no. (%)

 0 or 1

50 (74 %)

76 (55 %)

70 (70 %)

0.029

0.012

0.647

 2

14 (21 %)

42 (30 %)

26 (26 %)

   

 ≥3

4 (6 %)

20 (14 %)

4 (4 %)

   

CHA2DS2-VASc

 Mean score (±SD)

2.1 (±1.1)

2.7 (±1.4)

2.1 (±1.1)

0.001

0.001

0.837

Score—no. (%)

 0 or 1

20 (29 %)

26 (19 %)

30 (30 %)

0.009

0.003

0.993

 2

25 (37 %)

37 (27 %)

36 (36 %)

   

 3

17 (25 %)

36 (26 %)

24 (24 %)

   

 ≥4

6 (9 %)

39 (28 %)

10 (10 %)

   

 HAS-BLED

 Mean score (±SD)

1.4 (±0.8)

1.7 (±0.8)

1.4 (±0.8)

0.001

0.003

0.496

Score—no. (%)

 0 or 1

43 (63 %)

48 (35 %)

54 (54 %)

0.001

0.011

0.332

 2

19 (28 %)

73 (53 %)

39 (39 %)

   

 ≥3

6 (9 %)

17 (12 %)

7 (7 %)

   

LAA morphology—no. (%)

 Banded LAA (chicken wings)

37 (54 %)

92 (67 %)

81 (81 %)

0.002

0.005

<0.001

 Non-banded LAA (wind socks, cauliflower, cactus)

31 (46 %)

35 (25 %)

19 (19 %)

   

 Unknown

0 (0 %)

11 (8 %)

0 (0 %)

   

Medications at time of inclusion—no. (%)

 ACE inhibitor/ARB

41 (60 %)

99 (72 %)

68 (68 %)

0.113

0.568

0.327

 Amiodarone

4 (6 %)

21 (15 %)

9 (9 %)

0.069

0.171

0.564

 Aspirin

14 (21 %)

15 (11 %)

10 (10 %)

0.087

1

0.072

 Beta blocker

61 (90 %)

123 (89 %)

97 (97 %)

1

0.092

0.026

 Calcium antagonist

8 (12 %)

35 (25 %)

18 (18 %)

0.028

0.208

0.385

 Clopidogrel

0 (0 %)

3 (2 %)

0 (0 %)

0.552

0.266

1

 Cardiac glycosides

7 (10 %)

16 (12 %)

19 (19 %)

1

0.138

0.136

 Dronedarone

2 (3 %)

19 (14 %)

2 (2 %)

0.014

0.001

1

 Statin

32 (47 %)

65 (47 %)

33 (33 %)

1

0.077

0.033

 NSAR

16 (24 %)

15 (11 %)

9 (9 %)

0.022

0.67

0.014

 PPI

35 (51 %)

67 (49 %)

42 (42 %)

0.767

0.357

0.27

ACE angiotensin-converting enzyme, ARB angiotensin receptor blocker, LA left atrium, LAA left atrial appendage, LVEF left ventricular ejection fraction, NSAR non-steroidal anti-rheumatic agents, PPI proton-pump inhibitor, SD standard deviation, VKA vitamin K antagonists

Frequency of LA abnormalities

The groups of patients receiving VKA, dabigatran, and rivaroxaban medication did not yield significant differences with respect to frequency of LA abnormalities (Table 2). In summary, the frequency of LA abnormalities was lowest within the dabigatran group (3 %), followed by the rivaroxaban (5 %) and VKA group (9 %). A dense SEC (VKA: 1 %, dabigatran: 1 %, rivaroxaban: 2 %) was observed less frequently than a LA/LAA thrombus (VKA: 4 %, dabigatran: 0 %, rivaroxaban: 2 %), and a low LAAV of less than 20 cm/s (VKA: 4 %, dabigatran: 1 %, rivaroxaban: 1 %). The influence of VKA, dabigatran, and rivaroxaban on the risk of any LA abnormality was additionally analyzed by means of logistic regression models in order to prevent biased results due to imbalanced patient’s baseline characteristics. The results of the univariate and multivariate models are given in Table 3. The univariate models suggest that patients with CHADS2 score 2 and CHA2DS2-VASc score ≥4 have a significantly higher risk of any LA abnormality than patients with CHADS2-score 0–1 (OR 4.40, 95 % CI 1.54–12.54, p = 0.006) and CHA2DS2-VASc score 0–1 (OR 6.30, 95 % CI 1.28–30.95, p = 0.023). The multivariate model includes the CHADS2 score but not the CHA2DS2-VASc score. It suggests that patients with CHADS2 score 2 have a significantly higher risk of any LA abnormality than patients with CHADS2 score 0–1 (OR 4.07, 95 % CI 1.42–11.69, p = 0.009). Neither the univariate models nor the multivariate model indicate a significant difference between dabigatran and VKA and between rivaroxaban and VKA.
Table 2

Frequencies of LA abnormalities in the study population

 

VKA, n = 138 (45 %)

Dabigatran, n = 68 (22 %)

Rivaroxaban, n = 100 (33 %)

p value for difference between VKA and Dabigatran

p value for difference between VKA and Rivaroxaban

pvalue for difference between dabigatran and rivaroxaban

LA/LAA thrombus

5 (4 %)

0 (0 %)

2 (2 %)

0.173

0.515

0.702

Dense SEC

2 (1 %)

1 (1 %)

2 (2 %)

1

1

1

LAAV <20 cm/s

5 (4 %)

1 (1 %)

1 (1 %)

0.666

1

0.405

LA abnormality

12 (9 %)

2 (3 %)

5 (5 %)

0.15

0.702

0.318

LA left atrium, LAA left atrial appendage, LAAV left atrial appendage velocity, SEC spontaneous echo contrast, VKA vitamin K antagonists

Table 3

Univariate and multivariate logistic regression analyses of risk factors of any LA abnormality

 

Separate univariate models

Multivariate modela

Clinical variable

OR (95 % CI)

p value

OR (95 % CI)

p value

Dabigatran vs. VKA

0.32 (0.07–1.46)

0.141

0.40 (0.08–1.88)

0.245

Rivaroxaban vs. VKA

0.55 (0.19–1.62)

0.28

0.65 (0.22–1.98)

0.453

CHADS2: 2 vs. 0–1

4.40 (1.54–12.54)

0.006

4.07 (1.42–11.69)

0.009

CHADS2: ≥3 vs. 0–1

3.80 (0.89–16.16)

0.071

3.19 (0.73–13.99)

0.124

CHA2DS2-VASC: 2 vs. 0–1

1.99 (0.38–10.55)

0.419

  

CHA2DS2-VASC: 3 vs. 0–1

2.03 (0.36–11.41)

0.423

  

CHA2DS2-VASC: ≥4 vs. 0–1

6.30 (1.28–30.95)

0.023

  

HAS–BLED: 2 vs. 0–1

2.57 (0.87–7.60)

0.089

  

HAS–BLED: ≥3 vs. 0–1

3.11 (0.70–13.80)

0.135

  

Non-banded LAA vs. banded LAA

0.64 (0.21–1.99)

0.443

  

Unknown LAA vs. banded LAA

0.00 (0.00,∞)

0.99

  

Beta blocker

1.64 (0.21–12.84)

0.636

  

Calcium blocker

0.21 (0.03–1.61)

0.133

  

Dronedarone

1.49 (0.32–6.89)

0.61

  

Statin

1.24 (0.49–3.13)

0.657

  

NSAR

0.77 (0.17–3.47)

0.735

  

CI confidence interval, LAA left atrial appendage, NSAR non-steroidal anti-rheumatic agents, OR odds ratio, VKA vitamin K antagonists

aFinal model resulting from an all-subset variable selection based on Akaike’s Information Criterion; the medication group (dabigatran vs. VKA and rivaroxaban vs. VKA) was defined as fixed covariate, and the significant variables in column 1 were considered as possible covariates

Discussion

In the present study, we investigated the frequency of three echocardiographic risk factors for stroke and systemic embolism in patients treated with either dabigatran and rivaroxaban, or with VKAs. Both NOACs showed numerically lower statistically non-different results in comparison to VKA for prevention of LA abnormalities in a low- to mid-risk cohort.

The current European and American guidelines recommend in AF >48 h either a sufficient therapeutic anticoagulation (INR >2) for at least 3 weeks or TEE prior to cardioversion to exclude LAA thrombus. Interestingly, the guidelines do not clearly discriminate between oral anticoagulation with VKAs and NOACs [9, 10]. This recommendation is based on results of subgroup analyses of the RE-LY and ROCKET-AF as well as the separate X-VeRT trial [1315]. A recommendation regarding potential comparability of these different therapeutic anticoagulation regimens is based on subgroup analyses of the RE-LY as well as the ROCKET-AF trial. In the RE-LY trial, a cardioversion was performed in 1270 patients with AF. Stroke or systemic embolism at 30 days after cardioversion occurred in 0.8, 0.3, and 0.6 % of patients receiving dabigatran in a dose of 110 mg BID, 150 mg BID, and VKA, respectively [14]. In the ROCKET-AF trial, a cardioversion or catheter ablation was carried out in 321 patients. The incidence of stroke or systemic embolism at 30 days after cardioversion or ablation was 1.88 % in the rivaroxaban group and 1.86 % in the VKA group [15]. However, due to a markedly higher CHADS2 score, different study designs, and differences between TTRs, the event rates of the two NOACs could not be compared with each other. TTR in Rocket-AF was 55 % which was rather low and 64 % in the RE-LY study. A study published by Zylla and coworkers demonstrated in a high-risk population with a median CHA2DS2-VASc score of 4 that the prevalence of intracardiac thrombi under phenprocoumon was significantly higher (17.8 %) than in the dabigatran (3.8 %) or rivaroxaban group (4.1 %). Data about the TTR of VKA patients in which study are not available. Interestingly, subgroup analyses of the Rocket-AF data demonstrated that in rivaroxaban patients, the hazard ratio for the primary endpoint was above 1 when being compared with patients with a TTR of >67 %. Thus, sufficient VKA treatment may, despite other hurdles such as dependence of INR on oral vitamin K supply, higher interaction risk, and need for regular INR control, be comparable with NOACs as long as the TTR is high enough. This is especially important in patients where thromboembolic risk is per se not high. In our patients, TTR was 67 %. Despite clear trends that favor NOACs, we did not find significant differences between the two groups, even not with univariate or multivariate statistical models. Nevertheless, the results from the Zylla group imply that based on the relatively high incidence of LAA thrombi in a high-risk patient cohort, especially those under VKA, treatment may underlie a high risk of thromboembolic events during or after electrical cardioversion.

TEE is a moderately invasive method that allows a detailed evaluation of the structure and function of the LAA. It is accurate and the gold standard for identifying or excluding LA/LAA thrombus [29].

The incidence of LA/LAA thrombus under treatment with VKA depends on the patient population studied and different TTR values ranging from 1.5 to 17 % [3033]. In most studies, however, the incidence of LA/LAA thrombus was between 2 and 7 % [30, 32]. Thus, the present data (4 % in the VKA group) are in line with these studies. In the RE-LY trial, the rate of LA/LAA thrombus was 1.8, 1.2, and 1.1 % in the dabigatran group of with 110 mg BID, 150 mg BID, and VKA group, respectively [14]. Notably, we did not observe any thrombus in the dabigatran group. The rivaroxaban group showed a numerically slightly higher incidence of LA abnormalities than the dabigatran group, which was, however, statistically not significant.

It has been shown that patients with AF and dense SEC have a likelihood of stroke of 22 %/year, despite anticoagulation [21]. Dense SEC is described with a frequency of 8–35 % in patients with AF, depending on the patient population, type and effectiveness of anticoagulation, and CHADS2-/CHA2DS2-VASc Score [19, 3436]. Our results showed a relatively lower frequency of dense SEC (VKA: 1 %, dabigatran 1 %, rivaroxaban 2 %). A possible explanation for this difference is the high inter- and intraobserver variability in the grading of SEC [37].

Another important indicator for thromboembolic complications in patients with AF is the LAAV [34]. Reduction of the LAAV below 20 cm/s exhibited the highest association with stroke [38]. A LAAV less than 20 cm/s is found in 1 to 13 % of patients with AF [21, 34]. We observed an incidence of LAAV <20 cm/s that were numerically higher in patients receiving VKA (4 %) compared to patients receiving a NOAC (1 % for dabigatran and rivaroxaban). This observation is in line with the higher CHA2DS2-VASc score in this group.

It has been demonstrated that non-banded LAA is associated with lower LAAV and a higher frequency of SEC compared with banded LAA [39]. We found no significant association between the incidence of LA abnormalities and different LAA morphologies. Differences in the duration of AF/AFL in the different study populations could have, at least in part, contributed to these discrepancies.

Diastolic dysfunction is associated with a reduced LAA velocity, rate of SEC, and LAA thrombus in patient with non-valvular AF [40]. The impact of the three anticoagulatory drugs on LAA velocity, rate of SEC, and LAA thrombus in patients with non-valvular AF and diastolic dysfunction is unknown. Further studies are necessary to demonstrate the association between these parameters and LAA thrombus formation in patients with non-valvular AF under treatment with VKA and NOACs.

Several limitations of this study deserve attention. First, the number of investigated patients was relatively small. Second, there are further risk factors for stroke or systemic embolism in patients with AF, e.g., aortic plaques [19], which have not been addressed in the current trial. Third, we did not study patients being treated with Apixaban or edoxaban. Further studies should address the present approach in a larger patient cohort including apixaban and edoxaban patients. Fourth, the CHADS2/CHA2DS2-VASc scores are clinical classifications for predicting stroke in non-valvular AF and correlated with both dense SEC and LA/LAA thrombus [35]. The multivariate model in the present work also shows a close correlation between the CHADS2/CHA2DS2-VASc scores and LA-abnormalities. It is possible that the LA abnormalities are associated more with both scores than the anticoagulation drug.

Conclusion

This is the first study addressing the incidence of LA/LAA thrombus formation in a predominantly low- to mid-risk patients cohort being treated with dabigatran or rivaroxaban compared with VKAs at a TTR of >65 %. This study demonstrates that with respect to the incidence of echocardiographic risk factors for thromboembolic events, both dabigatran and rivaroxaban are not inferior to VKA.

Notes

Abbreviations

AF: 

atrial fibrillation

CHADS2

congestive heart failure, hypertension, age ≥75, diabetes mellitus, and prior stroke or transient ischemic attack (2 points)

CHA2DS2-VASc: 

congestive heart failure, hypertension, age (≥75: 2 points, 65–74: 1 point), diabetes mellitus, prior stroke or transient ischemic attack (2 points), vascular disease, sex category (female gender)

HAS-BLED: 

hypertension, abnormal renal or liver function, prior stroke, bleeding, labile INRs, elderly (age ≥65), drug therapy or alcohol intake

LA: 

left atrium

LAA: 

left atrial appendage

LAAV: 

left atrial appendage velocity

NOAC: 

non-vitamin K antagonist oral anticoagulants

SEC: 

spontaneous echo contrast

VKA: 

vitamin K antagonists

Declarations

Authors’ contributions

SR, TA, MK, and MR conceived the study, study design, and participated in literature search. SR, TA, and MK collected the data and evaluated the data in collaboration with MB. SR, MB, and MR performed data analysis, data interpretation, and wrote the manuscript. HT and JW co-wrote and revised the manuscript. All authors read and approved the final manuscript.

Acknowledgements

None.

Competing interests

The authors declare that they have no competing interests.

Availability of data and materials

Please contact author for data requests.

Ethics approval and consent to participate

The present study was approved by the research ethical committee of the University of Lübeck (No. 13-250). The study contains only retrospective data. Consent to participate was not required.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Department of Cardiovascular Medicine, University Hospital Muenster
(2)
Department of Cardiology/Angiology/Intensive Care Medicine, University Heart Center Luebeck
(3)
Institute of Biostatistics and Clinical Research, University of Muenster

References

  1. Benjamin EJ, Wolf PA, D’Agostino RB, Silbershatz H, Kannel WB, Levy D. Impact of atrial fibrillation on the risk of death: the Framingham heart study. Circulation. 1998;98(10):946–52.View ArticlePubMedGoogle Scholar
  2. Go AS, Hylek EM, Phillips KA, Chang Y, Henault LE, Selby JV, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study. JAMA. 2001;285(18):2370–5.View ArticlePubMedGoogle Scholar
  3. Vidaillet H, Granada JF, Po Chyou, Maassen K, Ortiz M, Pulido JN, et al. A population-based study of mortality among patients with atrial fibrillation or flutter. Am J Med. 2002;113(5):365–70.View ArticlePubMedGoogle Scholar
  4. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham study. Stroke. 1991;22(8):983–8.View ArticlePubMedGoogle Scholar
  5. Stewart S, Hart CL, Hole DJ, McMurray JJ. A population-based study of the long-term risks associated with atrial fibrillation: 20-year follow-up of the renfrew/paisley study. Am J Med. 2002;113(5):359–64.View ArticlePubMedGoogle Scholar
  6. Anonymous. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation analysis of pooled data from five randomized controlled trials. Arch Intern Med. 1994;154(13):1449–57.View ArticleGoogle Scholar
  7. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883–91.View ArticlePubMedGoogle Scholar
  8. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139–51.View ArticlePubMedGoogle Scholar
  9. Camm AJ, Lip GY, De Caterina R, Savelieva I, Atar D, Hohnloser SH, et al. Guidelines for the management of atrial fibrillation: the task force for the management of atrial fibrillation of the european society of cardiology (ESC). Europace. 2012;12(10):1360–420.Google Scholar
  10. January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JC Jr, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice guidelines and the heart rhythm society. Circulation. 2014;130(23):270–1.View ArticleGoogle Scholar
  11. Gallagher MM, Hennessy BJ, Edvardsson N, Hart CM, Shannon MS, Obel OA, et al. Embolic complications of direct current cardioversion of atrial arrhythmias: association with low intensity of anticoagulation at the time of cardioversion. J Am Coll Cardiol. 2002;40(5):926–33.View ArticlePubMedGoogle Scholar
  12. You JJ, Singer DE, Howard PA, Lane DA, Eckman MH, Fang MC, et al. Antithrombotic therapy for atrial fibrillation: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):531–75.View ArticleGoogle Scholar
  13. Cappato R, Ezekowitz MD, Klein AL, Camm AJ, Ma CS, Le Heuzey JY, et al. Rivaroxaban vs. vitamin K antagonists for cardioversion in atrial fibrillation. Eur Heart J. 2014;35(47):3346–55.View ArticlePubMedGoogle Scholar
  14. Nagarakanti R, Ezekowitz MD, Oldgren J, Yang S, Chernick M, Aikens TH, et al. Dabigatran versus warfarin in patients with atrial fibrillation: an analysis of patients undergoing cardioversion. Circulation. 2011;123(2):131–6.View ArticlePubMedGoogle Scholar
  15. Piccini JP, Stevens SR, Lokhnygina Y, Patel MR, Halperin JL, Singer DE, et al. Outcomes after cardioversion and atrial fibrillation ablation in patients treated with rivaroxaban and warfarin in the ROCKET AF trial. J Am Coll Cardiol. 2013;61(19):1998–2006.View ArticlePubMedGoogle Scholar
  16. Zylla MM, Pohlmeier M, Hess A, Mereles D, Kieser M, Bruckner T, et al. Prevalence of intracardiac thrombi under phenprocoumon, direct oral anticoagulants (dabigatran and rivaroxaban), and bridging therapy in patients with atrial fibrillation and flutter. Am J Cardiol. 2015;115(5):635–40.View ArticlePubMedGoogle Scholar
  17. Zabalgoitia M, et al. Transesophageal echocardiographic correlates of thromboembolism in high-risk patients with nonvalvular atrial fibrillation. The Stroke Prevention in Atrial Fibrillation Investigators Committee on Echocardiography. Ann Intern Med. 1998;128(8):639–47.View ArticleGoogle Scholar
  18. Fatkin D, Kelly RP. Feneley MP Relations between left atrial appendage blood flow velocity, spontaneous echocardiographic contrast and thromboembolic risk in vivo. J Am Coll Cardiol. 1994;23(4):961–9.View ArticlePubMedGoogle Scholar
  19. Zabalgoitia M, Halperin JL, Pearce LA, Blackshear JL, Asinger RW, Hart RG. Transesophageal echocardiographic correlates of clinical risk of thromboembolism in nonvalvular atrial fibrillation. Stroke prevention in atrial fibrillation III investigators. J Am Coll Cardiol. 1998;31(7):1622–6.View ArticlePubMedGoogle Scholar
  20. Takashima S, Nakagawa K, Hirai T, Dougu N, Taguchi Y, Sasahara E, et al. Transesophageal echocardiographic findings are independent and relevant predictors of ischemic stroke in patients with nonvalvular atrial fibrillation. J Clin Neurol. 2012;8(3):170–6.View ArticlePubMedPubMed CentralGoogle Scholar
  21. Bernhardt P, Schmidt H, Hammerstingl C, Lüderitz B, Omran H. Patients with atrial fibrillation and dense spontaneous echo contrast at high risk a prospective and serial follow-up over 12 months with transesophageal echocardiography and cerebral magnetic resonance imaging. J Am Coll Cardiol. 2005;45(11):1807–12.View ArticlePubMedGoogle Scholar
  22. Flachskampf FA, Klinghammer L. European Association of Echocardiography recommendations for assessment of valvular regurgitation: a correction. Eur J Echocardiogr. 2010;11(10):807–8.View ArticlePubMedGoogle Scholar
  23. Shanewise JS, Cheung AT, Aronson S, Stewart WJ, Weiss RL, Mark JB, et al. ASE/SCA guidelines for performing a comprehensive intraoperative multiplane transesophageal echocardiography examination: recommendations of the American Society of Echocardiography Council for Intraoperative Echocardiography and the Society of Cardiovascular Anesthesiologists Task Force for Certification in Perioperative Transesophageal Echocardiography. J Am Soc Echocardiogr. 1999;12(10):884–900.View ArticlePubMedGoogle Scholar
  24. Wang Y, Di Biase L, Horton RP, Nguyen T, Morhanty P, Natale A. Left atrial appendage studied by computed tomography to help planning for appendage closure device placement. J Cardiovasc Electrophysiol. 2010;21(9):973–82.View ArticlePubMedGoogle Scholar
  25. Leung DY, Davidson PM, Cranney GB, Walsh WF. Thromboembolic risks of left atrial thrombus detected by transesophageal echocardiogram. Am J Cardiol. 1997;79(5):626–9.View ArticlePubMedGoogle Scholar
  26. Agmon Y, Khandheria BK, Gentile F, Seward JB. Echocardiographic assessment of the left atrial appendage. J Am Coll Cardiol. 1999;34(7):1867–77.View ArticlePubMedGoogle Scholar
  27. Rosendaal FR, Cannegieter SC, van der Meer FJ, Briët E. A method to determine the optimal intensity of oral anticoagulant therapy. Thromb Haemost. 1993;69(3):236–9.PubMedGoogle Scholar
  28. Akaike H, Parzen E, Tanabe K. Selected papers of Hirotugu Akaike. New York: Springer; 1998.Google Scholar
  29. Beigel R, Wunderlich NC, Ho SY, Arsanjani R, Siegel RJ. The left atrial appendage: anatomy, function, and noninvasive evaluation. JACC Cardiovasc Imaging. 2014;7(12):1251–65.View ArticlePubMedGoogle Scholar
  30. Dorenkamp M, Sohns C, Vollmann D, Lüthje L, Seegers J, Wachter R, et al. Detection of left atrial thrombus during routine diagnostic work-up prior to pulmonary vein isolation for atrial fibrillation: role of transesophageal echocardiography and multidetector computed tomography. Int J Cardiol. 2011;163(1):26–33.View ArticlePubMedGoogle Scholar
  31. Ono K, Iwama M, Kawasaki M, Tanaka R, Watanabe T, Onishi N, et al. Motion of left atrial appendage as a determinant of thrombus formation in patients with a low CHADS2 score receiving warfarin for persistent nonvalvular atrial fibrillation. Cardiovasc Ultrasound. 2012;10:50.View ArticlePubMedPubMed CentralGoogle Scholar
  32. Saksena S, Sra J, Jordaens L, Kusumoto F, Knight B, Natale A, et al. A prospective comparison of cardiac imaging using intracardiac echocardiography with transesophageal echocardiography in patients with atrial fibrillation: the intracardiac echocardiography guided cardioversion helps interventional procedures study. Circ Arrhythm Electrophysiol. 2010;3(6):571–7.View ArticlePubMedGoogle Scholar
  33. Scherr D, Dalal D, Chilukuri K, Dong J, Spragg D, Henrikson CA, et al. Incidence and predictors of left atrial thrombus prior to catheter ablation of atrial fibrillation. J Cardiovasc Electrophysiol. 2009;20(4):379–84.View ArticlePubMedGoogle Scholar
  34. Cianfrocca C, Loricchio ML, Pelliccia F, Pasceri V, Auriti A, Bianconi L, et al. C-reactive protein and left atrial appendage velocity are independent determinants of the risk of thrombogenesis in patients with atrial fibrillation. Int J Cardiol. 2010;142(1):22–8.View ArticlePubMedGoogle Scholar
  35. Kleemann T, Becker T, Strauss M, Schneider S, Seidl K. Prevalence and clinical impact of left atrial thrombus and dense spontaneous echo contrast in patients with atrial fibrillation and low CHADS2 score. Eur J Echocardiogr. 2009;10(3):383–8.View ArticlePubMedGoogle Scholar
  36. Providência R, Botelho A, Trigo J, Quintal N, Nascimento J, Mota P, et al. Possible refinement of clinical thromboembolism assessment in patients with atrial fibrillation using echocardiographic parameters. Europace. 2012;14(1):36–45.View ArticlePubMedGoogle Scholar
  37. Fatkin D, Loupas T, Jacobs N, Feneley MP. Quantification of blood echogenicity: evaluation of a semiquantitative method of grading spontaneous echo contrast. Ultrasound Med Biol. 1995;21(9):1191–8.View ArticlePubMedGoogle Scholar
  38. Goldman ME, Pearce LA, Hart RG, Zabalgoitia M, Asinger RW, Safford R, et al. Pathophysiologic correlates of thromboembolism in nonvalvular atrial fibrillation: I. Reduced flow velocity in the left atrial appendage (The Stroke Prevention in Atrial Fibrillation [SPAF-III] study). J Am Soc Echocardiogr. 1999;12(12):1080–7.View ArticlePubMedGoogle Scholar
  39. Petersen M, Roehrich A, Balzer J, Shin DI, Meyer C, Kelm M, et al. Left atrial appendage morphology is closely associated with specific echocardiographic flow pattern in patients with atrial fibrillation. Europace. 2014;17(4):539–45.View ArticlePubMedGoogle Scholar
  40. Iwakura K, Okamura A, Koyama Y, Date M, Higuchi Y, Inoue K. Effect of elevated left ventricular diastolic filling pressure on the frequency of left atrial appendage thrombus in patients with nonvalvular atrial fibrillation. Am J Cardiol. 2011;107(3):417–22.View ArticlePubMedGoogle Scholar

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