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Abstract

Aims

Incidental detection of left atrial appendage (LAA) filling defects is a common finding on multi-detector computed tomography in aortic stenosis patients under evaluation for transcatheter aortic valve implantation (TAVI). We aimed to investigate the incidence of LAA filling defects before TAVI and its impact on clinical outcomes.

Methods and results

In a prospective registry, LAA filling defects were retrospectively evaluated and categorized into one of four sub-types: thrombus-like, heterogeneous, horizontal, and Hounsfield Unit (HU)-run-off. The primary endpoint was the composite of cardiovascular death or disabling stroke up to 1-year follow-up. Among 1621 patients undergoing TAVI between August 2007 and June 2018, LAA filling defects were present in 177 patients (11%), and categorized as thrombus-like in 22 (1.4%), heterogeneous in 37 (2.3%), horizontal in 80 (4.9%), and HU-run-off in 38 (2.4%). Compared to patients with normal LAA filling, patients with LAA filling defects had greater prevalence of atrial fibrillation (84.7% vs. 26.4%, P < 0.001) and history of cerebrovascular events (16.4% vs. 10.9%, P = 0.045). The primary endpoint occurred in 131 patients (9.2%) with normal LAA filling and in 36 patients (21.2%) with LAA filling defects (P < 0.001). Subgroup analysis suggested that the risk of disabling stroke was greatest in the thrombus-like pattern (23.0%), followed by the HU-run-off (8.0%), the heterogeneous (6.2%), and the horizontal pattern (1.2%).

Conclusion

LAA filling defects were observed in 11% of aortic stenosis patients undergoing TAVI and associated with an increased risk of cardiovascular death and disabling stroke up to 1 year following TAVI.

Trial Registration

https://www.clinicaltrials.gov. NCT01368250.

Graphical Abstract
Graphical Abstract
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transcatheter aortic valve, replacement, transcatheter, aortic valve, implantation, stroke, left, atrial appendage thrombus, left atrial appendage filling, defect, atria, l fibrillation

Introduction

Stroke is a devastating complication following transcatheter aortic valve implantation (TAVI) and continues to occur in up to 4% of patients at 30 days, and up to 6% of patients at 1 year despite rigorous pre-procedural planning, iterative improvements of delivery catheters, and adoption of a minimalist approach.1,2 Although the risk of cerebrovascular events is multifactorial, atrial fibrillation has emerged as one of the most relevant predictors of stroke following TAVI.2,3 Formation and embolization of left atrial appendage (LAA) thrombus (LAAT) have been suggested as one of the mechanisms of stroke in patients with atrial fibrillation.4

LAA filling defects as detected by multi-detector computed tomography (MDCT) are considered a correlate of thrombus or blood stagnation in the LAA, and a common incidental finding in patients with aortic stenosis undergoing MDCT during pre-procedural planning of TAVI. MDCT has an excellent diagnostic accuracy for the detection of LAAT as compared with transoesophageal echocardiography (TOE) with a negative predictive value of 100%.5 In a cohort study of 198 consecutive patients, LAA filling defects were documented in 11% of patients referred for consideration of TAVI.5 However, the clinical impact of LAA filling defects has not been well studied.6 The objective of the present study was to investigate the prevalence of LAA filling defects on pre-procedural MDCT in patients undergoing TAVI and its impact on clinical outcomes.

Methods

Study design and population

All patients undergoing TAVI at Bern University Hospital, Switzerland, are consecutively enrolled into a prospective institutional registry, which forms part of the Swiss TAVI registry (NCT01368250). The prospective registry was approved by the Bern cantonal ethics committee, and patients provided written informed consent to participate. The present analysis included patients that underwent TAVI between August 2007 and June 2018. For the purpose of the present analysis, patients were excluded if there was no pre-procedural MDCT performed, or if the image quality of the pre-procedural MDCT was poor. Patients with prior LAA closure devices or with congenital absence of LAA were also excluded from the analysis.

Assessment of LAA filling defects

Pre-TAVI MDCT examinations were performed as previously described.7 Each patient received an intravenous injection of 80–120 mL of contrast medium at a flow rate of 5 mL/s and image acquisition was performed during an inspiratory breath-hold in a cranio-caudal direction. Acquired MDCT images were transferred to a dedicated workstation (3mensio Structural Heart, 3mensio Medical Imaging BV, Bilthoven, The Netherlands) in the Corelab and evaluated by an independent investigator blinded to clinical history and outcomes. The presence or absence of LAA filling defects were firstly determined in the axial view (A) and further confirmed in the double oblique view (B) reconstructed by the build-in module for LAA assessment (Supplementary data online, Figure S1). In the presence of LAA filling defects, luminal attenuation in Hounsfield Unit (HU) was measured in the area of LAA filling defects and in the left atrium (LA), and the ratio of LAA to LA was calculated (Supplementary data online, Figure S1B). According to the visual appearance, LAA filling defects were categorized into a thrombus-like pattern, a horizontal pattern, a heterogeneous pattern, and a HU-run-off pattern primarily based on the axial view images (Figure 1). The thrombus-like pattern was characterized by the presence of a filling defect with a clearly demarkable borderline. In the case of a sharp horizontal border between the contrast agent and a filling defect, it was categorized as the horizontal pattern. If no clear borders of filling defects were demarkable, the pattern was categorized as the heterogeneous or HU-run-off pattern. The heterogeneous pattern was characterized by the appearance of mixed contrast enhancement and filling defects in the LAA. The HU-run-off pattern was defined by decreasing CT densities from dorsal to ventral direction in the LAA.8

Images of LAA filling defects. (A) Thrombus-like pattern: LAA filling defects with clearly delineated but not horizontal borderline with contrast agent. (B) Horizontal pattern: LAA filling defects with a sharp horizontal borderline between filling defects and contrast agent. (C) Heterogeneous pattern: Heterogeneous appearance of LAA filling defects with mixed contrast enhancement. (D) HU-run-off pattern: LAA filling defects with decreasing CT densities from dorsal to ventral direction in the LAA.
Figure 1

Images of LAA filling defects. (A) Thrombus-like pattern: LAA filling defects with clearly delineated but not horizontal borderline with contrast agent. (B) Horizontal pattern: LAA filling defects with a sharp horizontal borderline between filling defects and contrast agent. (C) Heterogeneous pattern: Heterogeneous appearance of LAA filling defects with mixed contrast enhancement. (D) HU-run-off pattern: LAA filling defects with decreasing CT densities from dorsal to ventral direction in the LAA.

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Antithrombotic therapy after TAVI

The default antithrombotic therapy after TAVI was 6 months dual-antiplatelet therapy with aspirin and P2Y12 inhibitors followed by life-long single antiplatelet therapy in accordance with current European guideline.9 In patients with indication for oral anticoagulants, vitamin K antagonist or non-Vitamin K antagonist oral anticoagulants were used in combination with single antiplatelet therapy by default. The antithrombotic regimen was, however, ultimately left to the discretion of the operator given the individual risk of thromboembolism and bleeding. LAA filling defects were not systematically assessed and rarely taken into consideration during the pre-procedural evaluation.

Data collection and clinical endpoints

Baseline clinical, procedural, and follow-up data were entered into a dedicated database, independently held at the CTU of the University of Bern. Clinical follow-up data at 30 days and at 1 year were obtained by the use of standardized interviews, documentation from referring physicians, and hospital discharge summaries. All adverse events were systematically collected and adjudicated by a dedicated clinical event committee based on the updated Valve Academic Research Consortium criteria.10 When a neurological event was suspected, patients were examined by a senior neurologist and underwent diagnostic imaging tests as required. Stroke and transient ischaemic attack (TIA) were defined in accordance with the recommendation by the Academic Research Consortium Initiative,11 and stroke was further sub-divided into disabling and non-disabling stroke.10

The primary endpoint was a composite of cardiovascular death or disabling stroke at 1 year after TAVI. Secondary endpoints included all-cause and cardiovascular death, cerebrovascular events, myocardial infarction, and major or life-threatening bleeding at 30 days and 1 year after TAVI.

Statistical analysis

Categorical variables are represented as frequencies and percentages and the differences between groups are evaluated with the χ2 test or Fisher’s exact test. Continuous measures are presented as mean values ± standard deviation (SD) and compared between groups using t-test. Time-to-event curves were depicted using the Kaplan–Meier method. Univariate Cox proportional hazards model was used to calculate hazard ratios (HR) and 95% confidence intervals (95% CI) for the clinical outcomes. Multivariable Cox regression was performed to identify independent predictors of the primary endpoint, using two models. All clinical baseline variables were tested for entry into a simplified model with a P-value threshold of <0.10. Assumed mean or modal values were used for the multivariate analyses in the following missing values; body mass index (n = 5), left ventricular ejection fraction (n = 27), and chronic kidney disease (n = 3). In all time-to-event analyses, data for a patient were censored at the time of the first event that occurred in that patient. We also performed subgroup analyses according to LAA filling defects pattern. All statistical tests were two-sided and P-values of <0.05 were considered significant. Statistical analyses were performed using Stata 15.1 (StataCorp, College Station, TX, USA).

Results

Studied population and baseline characteristics

Among 2066 consecutive patients enrolled into the institutional TAVI registry, 1634 patients had adequate MDCT images to assess the presence or absence of LAA filling defects. Of these, 12 patients with prior LAA closure device implantation and 1 patient with congenital absence of LAA were excluded. Among the remaining 1621 patients analysed for the present study, LAA filling defects were detected in 177 patients (11%) and categorized as thrombus-like in 22 (1.4%), heterogeneous in 37 (2.3%), horizontal in 80 (4.9%), and HU-run-off in 38 patients (2.4%) (Figure 1). The horizontal pattern was the most frequent manifestation of LAA filling defects, accounting for 45% of all cases.

Baseline characteristics according to the presence or absence of LAA filling defects are summarized in Table 1. LAA filling defects were less common in female (44.1% vs. 53.7%, P = 0.02), and more often observed in patients with atrial fibrillation/flutter (84.7% vs. 26.4%, P < 0.001), and those with previous cerebrovascular events (16.4% vs. 10.9%, P = 0.045). The use of oral anticoagulants was more common in patients with LAA filling defects compared to those with normal LAA filling. Patients with LAA filling defects had a lower LVEF (49.7 ± 15.0 vs. 55.9 ± 13.9, P < 0.001), a lower mean gradient (36.4 ± 16.4 vs. 41.6 ± 17.8, P < 0.001), and a higher e/eʹ ratio (28.0 ± 12.6 vs. 20.5 ± 11.1, P = 0.002). Baseline characteristics stratified by the presence or absence of atrial fibrillation/flutter and LAA filling defects are provided in Supplementary data online, Table S1. The prevalence of atrial fibrillation/flutter, average luminal attenuation of LAA filling defects and the LA, and HU ratio (LAA/LA) for each LAA filling defects sub-type are summarized in Supplementary data online, Table S2. Across each LAA filling defects pattern, the prevalence of atrial fibrillation/flutter ranged from 73.0% to 89.5%. The mean HU of LAA filling defects was 120.3 ± 77.7 and the mean HU ratio was 0.23 ± 0.15. Antithrombotic management at follow-up according to the presence or absence of LAA filling defects are summarized in Supplementary data online, Table S3. While patients with LAA filling defects were more frequently treated with oral anticoagulants than those with normal LAA filling, about 20% of patients with LAA filling defects did not receive any oral anticoagulants throughout the follow-up period.

Table 1
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Baseline characteristics of the studied population

All patients (n = 1621)Normal LAA filling (n = 1444)LAA filling defects (n = 177)P-value
Age (years)82.18 ± 6.0082.12 ± 5.9982.68 ± 6.090.25
Female gender (n, %)853 (52.6)775 (53.7)78 (44.1)0.02
Body mass index (kg/cm²)26.55 ± 5.2726.55 ± 5.2926.57 ± 5.080.97
STS PROM5.33 ± 3.535.30 ± 3.555.55 ± 3.350.37
Hypertension (n, %)1379 (85.1)1223 (84.7)156 (88.1)0.26
Diabetes mellitus (n, %)394 (24.3)342 (23.7)52 (29.4)0.11
CKD (eGFR < 60) (n, %)1081 (66.8)954 (66.2)127 (71.8)0.15
Atrial fibrillation/flutter (n, %)531 (32.8)381 (26.4)150 (84.7)<0.001
Coronary artery disease (n, %)1006 (62.1)902 (62.5)104 (58.8)0.37
History of CVEs (n, %)187 (11.5)158 (10.9)29 (16.4)0.045
Peripheral artery disease (n, %)217 (13.4)186 (12.9)31 (17.5)0.10
Echocardiographic data
 LVEF (%)55.26 ± 14.1955.94 ± 13.9449.69 ± 15.04<0.001
 Aortic valve area (cm2)0.66 ± 0.250.66 ± 0.250.66 ± 0.270.93
 Transaortic mean gradient (mmHg)41.0 ± 17.741.6 ± 17.836.4 ± 16.4<0.001
 Average E/eʹ ratio20.9 ± 11.320.5 ± 11.128.0 ± 12.60.002
 Moderate/severe MR (n, %)235 (19.5)211 (19.6)24 (18.5)0.82
Medications at baseline (n, %)
 Antiplatelet therapy only909 (56.1)872 (60.4)37 (20.9)<0.001
 Oral anticoagulant only332 (20.5)238 (16.5)94 (53.1)<0.001
 Oral anticoagulant + antiplatelet therapy141 (8.7)108 (7.5)33 (18.6)<0.001
 None238 (14.7)225 (15.6)13 (7.3)0.002
All patients (n = 1621)Normal LAA filling (n = 1444)LAA filling defects (n = 177)P-value
Age (years)82.18 ± 6.0082.12 ± 5.9982.68 ± 6.090.25
Female gender (n, %)853 (52.6)775 (53.7)78 (44.1)0.02
Body mass index (kg/cm²)26.55 ± 5.2726.55 ± 5.2926.57 ± 5.080.97
STS PROM5.33 ± 3.535.30 ± 3.555.55 ± 3.350.37
Hypertension (n, %)1379 (85.1)1223 (84.7)156 (88.1)0.26
Diabetes mellitus (n, %)394 (24.3)342 (23.7)52 (29.4)0.11
CKD (eGFR < 60) (n, %)1081 (66.8)954 (66.2)127 (71.8)0.15
Atrial fibrillation/flutter (n, %)531 (32.8)381 (26.4)150 (84.7)<0.001
Coronary artery disease (n, %)1006 (62.1)902 (62.5)104 (58.8)0.37
History of CVEs (n, %)187 (11.5)158 (10.9)29 (16.4)0.045
Peripheral artery disease (n, %)217 (13.4)186 (12.9)31 (17.5)0.10
Echocardiographic data
 LVEF (%)55.26 ± 14.1955.94 ± 13.9449.69 ± 15.04<0.001
 Aortic valve area (cm2)0.66 ± 0.250.66 ± 0.250.66 ± 0.270.93
 Transaortic mean gradient (mmHg)41.0 ± 17.741.6 ± 17.836.4 ± 16.4<0.001
 Average E/eʹ ratio20.9 ± 11.320.5 ± 11.128.0 ± 12.60.002
 Moderate/severe MR (n, %)235 (19.5)211 (19.6)24 (18.5)0.82
Medications at baseline (n, %)
 Antiplatelet therapy only909 (56.1)872 (60.4)37 (20.9)<0.001
 Oral anticoagulant only332 (20.5)238 (16.5)94 (53.1)<0.001
 Oral anticoagulant + antiplatelet therapy141 (8.7)108 (7.5)33 (18.6)<0.001
 None238 (14.7)225 (15.6)13 (7.3)0.002

CKD, chronic kidney disease; CVEs, cerebrovascular events; eGFR, estimated glomerular filtration rate; LVEF, left ventricular ejection fraction; MR, mitral regurgitation; STS-PROM, Society of Thoracic Surgeons Predicted Risk of Mortality.

Antiplatelet therapy includes both single and dual antiplatelet therapy.

Table 1
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Baseline characteristics of the studied population

All patients (n = 1621)Normal LAA filling (n = 1444)LAA filling defects (n = 177)P-value
Age (years)82.18 ± 6.0082.12 ± 5.9982.68 ± 6.090.25
Female gender (n, %)853 (52.6)775 (53.7)78 (44.1)0.02
Body mass index (kg/cm²)26.55 ± 5.2726.55 ± 5.2926.57 ± 5.080.97
STS PROM5.33 ± 3.535.30 ± 3.555.55 ± 3.350.37
Hypertension (n, %)1379 (85.1)1223 (84.7)156 (88.1)0.26
Diabetes mellitus (n, %)394 (24.3)342 (23.7)52 (29.4)0.11
CKD (eGFR < 60) (n, %)1081 (66.8)954 (66.2)127 (71.8)0.15
Atrial fibrillation/flutter (n, %)531 (32.8)381 (26.4)150 (84.7)<0.001
Coronary artery disease (n, %)1006 (62.1)902 (62.5)104 (58.8)0.37
History of CVEs (n, %)187 (11.5)158 (10.9)29 (16.4)0.045
Peripheral artery disease (n, %)217 (13.4)186 (12.9)31 (17.5)0.10
Echocardiographic data
 LVEF (%)55.26 ± 14.1955.94 ± 13.9449.69 ± 15.04<0.001
 Aortic valve area (cm2)0.66 ± 0.250.66 ± 0.250.66 ± 0.270.93
 Transaortic mean gradient (mmHg)41.0 ± 17.741.6 ± 17.836.4 ± 16.4<0.001
 Average E/eʹ ratio20.9 ± 11.320.5 ± 11.128.0 ± 12.60.002
 Moderate/severe MR (n, %)235 (19.5)211 (19.6)24 (18.5)0.82
Medications at baseline (n, %)
 Antiplatelet therapy only909 (56.1)872 (60.4)37 (20.9)<0.001
 Oral anticoagulant only332 (20.5)238 (16.5)94 (53.1)<0.001
 Oral anticoagulant + antiplatelet therapy141 (8.7)108 (7.5)33 (18.6)<0.001
 None238 (14.7)225 (15.6)13 (7.3)0.002
All patients (n = 1621)Normal LAA filling (n = 1444)LAA filling defects (n = 177)P-value
Age (years)82.18 ± 6.0082.12 ± 5.9982.68 ± 6.090.25
Female gender (n, %)853 (52.6)775 (53.7)78 (44.1)0.02
Body mass index (kg/cm²)26.55 ± 5.2726.55 ± 5.2926.57 ± 5.080.97
STS PROM5.33 ± 3.535.30 ± 3.555.55 ± 3.350.37
Hypertension (n, %)1379 (85.1)1223 (84.7)156 (88.1)0.26
Diabetes mellitus (n, %)394 (24.3)342 (23.7)52 (29.4)0.11
CKD (eGFR < 60) (n, %)1081 (66.8)954 (66.2)127 (71.8)0.15
Atrial fibrillation/flutter (n, %)531 (32.8)381 (26.4)150 (84.7)<0.001
Coronary artery disease (n, %)1006 (62.1)902 (62.5)104 (58.8)0.37
History of CVEs (n, %)187 (11.5)158 (10.9)29 (16.4)0.045
Peripheral artery disease (n, %)217 (13.4)186 (12.9)31 (17.5)0.10
Echocardiographic data
 LVEF (%)55.26 ± 14.1955.94 ± 13.9449.69 ± 15.04<0.001
 Aortic valve area (cm2)0.66 ± 0.250.66 ± 0.250.66 ± 0.270.93
 Transaortic mean gradient (mmHg)41.0 ± 17.741.6 ± 17.836.4 ± 16.4<0.001
 Average E/eʹ ratio20.9 ± 11.320.5 ± 11.128.0 ± 12.60.002
 Moderate/severe MR (n, %)235 (19.5)211 (19.6)24 (18.5)0.82
Medications at baseline (n, %)
 Antiplatelet therapy only909 (56.1)872 (60.4)37 (20.9)<0.001
 Oral anticoagulant only332 (20.5)238 (16.5)94 (53.1)<0.001
 Oral anticoagulant + antiplatelet therapy141 (8.7)108 (7.5)33 (18.6)<0.001
 None238 (14.7)225 (15.6)13 (7.3)0.002

CKD, chronic kidney disease; CVEs, cerebrovascular events; eGFR, estimated glomerular filtration rate; LVEF, left ventricular ejection fraction; MR, mitral regurgitation; STS-PROM, Society of Thoracic Surgeons Predicted Risk of Mortality.

Antiplatelet therapy includes both single and dual antiplatelet therapy.

Clinical outcomes

Clinical follow-up was completed in 1598 patients (98.6%). Clinical outcomes at 30 days and 1 year according to the presence or absence of LAA filling defects are summarized in Table 2. At 30 days, patients with LAA filling defects had a higher incidence of the composite endpoint of cardiovascular death or disabling stroke compared to those with normal LAA filling (6.8% vs. 3.5%, P = 0.04). There was no difference in the incidence of all-cause (4.0% vs. 2.6%, P = 0.31) and cardiovascular death (4.0% vs. 2.2%, P = 0.14). The incidence of cerebrovascular events was higher in patients with LAA filling defects compared to those with normal LAA filling (7.4% vs. 3.6%, P = 0.02); the difference was primarily driven by the higher incidence of disabling stroke (4.5% vs. 1.9%, P = 0.03) (Figure 2).

Incidence of cerebrovascular events at 30 days and 1 year after TAVI.
Figure 2

Incidence of cerebrovascular events at 30 days and 1 year after TAVI.

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Table 2
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Clinical outcomes at 30 days and 1 year after TAVI according to the presence of LAA filling defects

Normal LAA filling (n = 1444)LAA filling defects (n = 177)HR (95% CI)P-value
At 30 days
 Composite of cardiovascular death and disabling stroke (n, %)51 (3.5)12 (6.8)1.95 (1.04–3.66)0.038
  All-cause death (n, %)38 (2.6)7 (4.0)1.52 (0.68–3.40)0.31
  Cardiovascular death (n, %)31 (2.2)7 (4.0)1.86 (0.82–4.22)0.14
 Cerebrovascular event (n, %)51 (3.6)13 (7.4)2.12 (1.16–3.91)0.02
  Any stroke (n, %)43 (3.0)11 (6.2)2.12 (1.09–4.12)0.03
  Disabling stroke (n, %)27 (1.9)8 (4.5)2.44 (1.11–5.38)0.03
  Non-disabling stroke (n, %)16 (1.1)3 (1.7)1.54 (0.45–5.27)0.50
  Transient ischaemic attack (n, %)8 (0.6)2 (1.1)2.05 (0.44–9.65)0.36
 Myocardial infarction (n, %)10 (0.7)2 (1.1)1.63 (0.36–7.45)0.53
 Major or life-threatening bleeding (n, %)265 (18.4)29 (16.5)0.89 (0.60–1.30)0.53
At 1 year
 Composite of cardiovascular death and disabling stroke (n, %)131 (9.2)36 (21.2)2.46 (1.70–3.55)<0.001
  All-cause death (n, %)147 (10.3)40 (23.2)2.41 (1.70–3.42)<0.001
  Cardiovascular death (n, %)101 (7.2)29 (17.2)2.53 (1.68–3.83)<0.001
 Cerebrovascular event (n, %)79 (5.6)18 (10.7)1.99 (1.19–3.32)0.009
  Any stroke (n, %)66 (4.7)15 (8.9)1.97 (1.12–3.45)0.02
  Disabling stroke (n, %)43 (3.1)11 (6.5)2.20 (1.13–4.27)0.02
  Non-disabling stroke (n, %)25 (1.8)4 (2.4)1.37 (0.48–3.93)0.56
  Transient ischaemic attack (n, %)13 (0.9)3 (1.8)1.97 (0.56–6.90)0.29
 Myocardial infarction (n, %)25 (1.8)4 (2.6)1.41 (0.49–4.05)0.53
 Major or life-threatening bleeding (n, %)307 (21.4)40 (23.6)1.07 (0.77–1.49)0.69
Normal LAA filling (n = 1444)LAA filling defects (n = 177)HR (95% CI)P-value
At 30 days
 Composite of cardiovascular death and disabling stroke (n, %)51 (3.5)12 (6.8)1.95 (1.04–3.66)0.038
  All-cause death (n, %)38 (2.6)7 (4.0)1.52 (0.68–3.40)0.31
  Cardiovascular death (n, %)31 (2.2)7 (4.0)1.86 (0.82–4.22)0.14
 Cerebrovascular event (n, %)51 (3.6)13 (7.4)2.12 (1.16–3.91)0.02
  Any stroke (n, %)43 (3.0)11 (6.2)2.12 (1.09–4.12)0.03
  Disabling stroke (n, %)27 (1.9)8 (4.5)2.44 (1.11–5.38)0.03
  Non-disabling stroke (n, %)16 (1.1)3 (1.7)1.54 (0.45–5.27)0.50
  Transient ischaemic attack (n, %)8 (0.6)2 (1.1)2.05 (0.44–9.65)0.36
 Myocardial infarction (n, %)10 (0.7)2 (1.1)1.63 (0.36–7.45)0.53
 Major or life-threatening bleeding (n, %)265 (18.4)29 (16.5)0.89 (0.60–1.30)0.53
At 1 year
 Composite of cardiovascular death and disabling stroke (n, %)131 (9.2)36 (21.2)2.46 (1.70–3.55)<0.001
  All-cause death (n, %)147 (10.3)40 (23.2)2.41 (1.70–3.42)<0.001
  Cardiovascular death (n, %)101 (7.2)29 (17.2)2.53 (1.68–3.83)<0.001
 Cerebrovascular event (n, %)79 (5.6)18 (10.7)1.99 (1.19–3.32)0.009
  Any stroke (n, %)66 (4.7)15 (8.9)1.97 (1.12–3.45)0.02
  Disabling stroke (n, %)43 (3.1)11 (6.5)2.20 (1.13–4.27)0.02
  Non-disabling stroke (n, %)25 (1.8)4 (2.4)1.37 (0.48–3.93)0.56
  Transient ischaemic attack (n, %)13 (0.9)3 (1.8)1.97 (0.56–6.90)0.29
 Myocardial infarction (n, %)25 (1.8)4 (2.6)1.41 (0.49–4.05)0.53
 Major or life-threatening bleeding (n, %)307 (21.4)40 (23.6)1.07 (0.77–1.49)0.69
Table 2
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Clinical outcomes at 30 days and 1 year after TAVI according to the presence of LAA filling defects

Normal LAA filling (n = 1444)LAA filling defects (n = 177)HR (95% CI)P-value
At 30 days
 Composite of cardiovascular death and disabling stroke (n, %)51 (3.5)12 (6.8)1.95 (1.04–3.66)0.038
  All-cause death (n, %)38 (2.6)7 (4.0)1.52 (0.68–3.40)0.31
  Cardiovascular death (n, %)31 (2.2)7 (4.0)1.86 (0.82–4.22)0.14
 Cerebrovascular event (n, %)51 (3.6)13 (7.4)2.12 (1.16–3.91)0.02
  Any stroke (n, %)43 (3.0)11 (6.2)2.12 (1.09–4.12)0.03
  Disabling stroke (n, %)27 (1.9)8 (4.5)2.44 (1.11–5.38)0.03
  Non-disabling stroke (n, %)16 (1.1)3 (1.7)1.54 (0.45–5.27)0.50
  Transient ischaemic attack (n, %)8 (0.6)2 (1.1)2.05 (0.44–9.65)0.36
 Myocardial infarction (n, %)10 (0.7)2 (1.1)1.63 (0.36–7.45)0.53
 Major or life-threatening bleeding (n, %)265 (18.4)29 (16.5)0.89 (0.60–1.30)0.53
At 1 year
 Composite of cardiovascular death and disabling stroke (n, %)131 (9.2)36 (21.2)2.46 (1.70–3.55)<0.001
  All-cause death (n, %)147 (10.3)40 (23.2)2.41 (1.70–3.42)<0.001
  Cardiovascular death (n, %)101 (7.2)29 (17.2)2.53 (1.68–3.83)<0.001
 Cerebrovascular event (n, %)79 (5.6)18 (10.7)1.99 (1.19–3.32)0.009
  Any stroke (n, %)66 (4.7)15 (8.9)1.97 (1.12–3.45)0.02
  Disabling stroke (n, %)43 (3.1)11 (6.5)2.20 (1.13–4.27)0.02
  Non-disabling stroke (n, %)25 (1.8)4 (2.4)1.37 (0.48–3.93)0.56
  Transient ischaemic attack (n, %)13 (0.9)3 (1.8)1.97 (0.56–6.90)0.29
 Myocardial infarction (n, %)25 (1.8)4 (2.6)1.41 (0.49–4.05)0.53
 Major or life-threatening bleeding (n, %)307 (21.4)40 (23.6)1.07 (0.77–1.49)0.69
Normal LAA filling (n = 1444)LAA filling defects (n = 177)HR (95% CI)P-value
At 30 days
 Composite of cardiovascular death and disabling stroke (n, %)51 (3.5)12 (6.8)1.95 (1.04–3.66)0.038
  All-cause death (n, %)38 (2.6)7 (4.0)1.52 (0.68–3.40)0.31
  Cardiovascular death (n, %)31 (2.2)7 (4.0)1.86 (0.82–4.22)0.14
 Cerebrovascular event (n, %)51 (3.6)13 (7.4)2.12 (1.16–3.91)0.02
  Any stroke (n, %)43 (3.0)11 (6.2)2.12 (1.09–4.12)0.03
  Disabling stroke (n, %)27 (1.9)8 (4.5)2.44 (1.11–5.38)0.03
  Non-disabling stroke (n, %)16 (1.1)3 (1.7)1.54 (0.45–5.27)0.50
  Transient ischaemic attack (n, %)8 (0.6)2 (1.1)2.05 (0.44–9.65)0.36
 Myocardial infarction (n, %)10 (0.7)2 (1.1)1.63 (0.36–7.45)0.53
 Major or life-threatening bleeding (n, %)265 (18.4)29 (16.5)0.89 (0.60–1.30)0.53
At 1 year
 Composite of cardiovascular death and disabling stroke (n, %)131 (9.2)36 (21.2)2.46 (1.70–3.55)<0.001
  All-cause death (n, %)147 (10.3)40 (23.2)2.41 (1.70–3.42)<0.001
  Cardiovascular death (n, %)101 (7.2)29 (17.2)2.53 (1.68–3.83)<0.001
 Cerebrovascular event (n, %)79 (5.6)18 (10.7)1.99 (1.19–3.32)0.009
  Any stroke (n, %)66 (4.7)15 (8.9)1.97 (1.12–3.45)0.02
  Disabling stroke (n, %)43 (3.1)11 (6.5)2.20 (1.13–4.27)0.02
  Non-disabling stroke (n, %)25 (1.8)4 (2.4)1.37 (0.48–3.93)0.56
  Transient ischaemic attack (n, %)13 (0.9)3 (1.8)1.97 (0.56–6.90)0.29
 Myocardial infarction (n, %)25 (1.8)4 (2.6)1.41 (0.49–4.05)0.53
 Major or life-threatening bleeding (n, %)307 (21.4)40 (23.6)1.07 (0.77–1.49)0.69

At 1 year, patients with LAA filling defects had a higher incidence of the primary endpoint compared to those with normal LAA filling (21.2% vs. 9.2%, P < 0.001) (Figure 3). Figure 4 displays the Kaplan–Meier curves for secondary endpoints at 1 year. The cumulative incidence of all-cause and cardiovascular death was two-fold higher in patients with LAA filling defects than those with normal LAA filling (23.2% vs. 10.3% and 17.2% vs. 7.2% respectively, P < 0.001 for both). Cerebrovascular events and disabling stroke occurred more frequently in patients with LAA filling defects compared to those with normal LAA filling (10.7% vs. 5.6%, P = 0.009; 6.5% vs. 3.1%, P = 0.02; respectively). In multivariable analyses, LAA filling defects were independently associated with a higher risk of the primary endpoint in both the full model (adjusted HR 1.86, 95% CI 1.22–2.84; P = 0.004) and the simplified model (adjusted HR 1.93, 95% CI 1.28–2.92; P = 0.002) (Table 3). Sub-group analyses for the impact of LAA filling defects on clinical outcomes stratified by the presence or absence of atrial fibrillation/flutter, preserved LVEF (≥50%), or the use of oral anticoagulants at discharge are shown in Figure 5. The impact on the primary endpoint was more pronounced in patients without atrial fibrillation/flutter (P for interaction = 0.03) or those without oral anticoagulants at discharge (P for interaction = 0.003), while it was consistent across LVEF sub-groups (P for interaction = 0.08).

Kaplan–Meier curves for the primary endpoint. The yellow line indicates patients with LAA filling defects. The green line indicates patients with normal LAA filling.
Figure 3

Kaplan–Meier curves for the primary endpoint. The yellow line indicates patients with LAA filling defects. The green line indicates patients with normal LAA filling.

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Kaplan–Meier curves for secondary endpoints. Time-to-event curves are shown for all-cause death (A), cardiovascular death (B), cerebrovascular events (C), and disabling stroke (D). The yellow line indicates patients with LAA filling defects. The green line indicates patients with normal LAA filling.
Figure 4

Kaplan–Meier curves for secondary endpoints. Time-to-event curves are shown for all-cause death (A), cardiovascular death (B), cerebrovascular events (C), and disabling stroke (D). The yellow line indicates patients with LAA filling defects. The green line indicates patients with normal LAA filling.

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Impact of LAA filling defects on outcomes stratified by sub-groups (atrial fibrillation, preserved LVEF, OAC).
Figure 5

Impact of LAA filling defects on outcomes stratified by sub-groups (atrial fibrillation, preserved LVEF, OAC).

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Table 3
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Multivariable analysis for the composite primary endpoint of cardiovascular mortality and disabling stroke at 1 year after TAVI

Full modelAdjusted HR (95% CI)P-valueSimplified modelAdjusted HR (95% CI)P-value
LAA filling defects1.86 (1.2–2.84)0.004LAA filling defects1.93 (1.28–2.92)0.002
Age (years)1.01 (0.98–1.04)0.41STS PROM1.08 (1.05–1.12)<0.001
Gender (female)0.90 (0.65–1.26)0.55Hypertension0.58 (0.39–0.85)0.005
Body mass index (kg/cm2)1.01 (0.97–1.04)0.75History of CVEs1.61 (1.09–2.39)0.02
STS PROM1.07 (1.03–1.11)<0.001Atrial fibrillation/flutter1.56 (1.11–2.19)0.01
Hypertension0.54 (0.37–0.81)0.003
Diabetes mellitus1.10 (0.76–1.58)0.62
CKD (GFR < 60)1.13 (0.76–1.68)0.55
Atrial fibrillation/flutter1.45 (0.97–2.16)0.07
Coronary artery disease1.21 (0.85–1.72)0.28
History of CVEs1.54 (1.03–2.31)0.04
Peripheral artery disease1.34 (0.89–2.00)0.16
LVEF (%)1.00 (0.99–1.01)0.75
Use of OAC1.11 (0.75–1.66)0.60
Full modelAdjusted HR (95% CI)P-valueSimplified modelAdjusted HR (95% CI)P-value
LAA filling defects1.86 (1.2–2.84)0.004LAA filling defects1.93 (1.28–2.92)0.002
Age (years)1.01 (0.98–1.04)0.41STS PROM1.08 (1.05–1.12)<0.001
Gender (female)0.90 (0.65–1.26)0.55Hypertension0.58 (0.39–0.85)0.005
Body mass index (kg/cm2)1.01 (0.97–1.04)0.75History of CVEs1.61 (1.09–2.39)0.02
STS PROM1.07 (1.03–1.11)<0.001Atrial fibrillation/flutter1.56 (1.11–2.19)0.01
Hypertension0.54 (0.37–0.81)0.003
Diabetes mellitus1.10 (0.76–1.58)0.62
CKD (GFR < 60)1.13 (0.76–1.68)0.55
Atrial fibrillation/flutter1.45 (0.97–2.16)0.07
Coronary artery disease1.21 (0.85–1.72)0.28
History of CVEs1.54 (1.03–2.31)0.04
Peripheral artery disease1.34 (0.89–2.00)0.16
LVEF (%)1.00 (0.99–1.01)0.75
Use of OAC1.11 (0.75–1.66)0.60

Assumed mean or modal values for missing data, missing were: BMI n = 5, LVEF n = 27, renal failure n = 3.

Table 3
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Multivariable analysis for the composite primary endpoint of cardiovascular mortality and disabling stroke at 1 year after TAVI

Full modelAdjusted HR (95% CI)P-valueSimplified modelAdjusted HR (95% CI)P-value
LAA filling defects1.86 (1.2–2.84)0.004LAA filling defects1.93 (1.28–2.92)0.002
Age (years)1.01 (0.98–1.04)0.41STS PROM1.08 (1.05–1.12)<0.001
Gender (female)0.90 (0.65–1.26)0.55Hypertension0.58 (0.39–0.85)0.005
Body mass index (kg/cm2)1.01 (0.97–1.04)0.75History of CVEs1.61 (1.09–2.39)0.02
STS PROM1.07 (1.03–1.11)<0.001Atrial fibrillation/flutter1.56 (1.11–2.19)0.01
Hypertension0.54 (0.37–0.81)0.003
Diabetes mellitus1.10 (0.76–1.58)0.62
CKD (GFR < 60)1.13 (0.76–1.68)0.55
Atrial fibrillation/flutter1.45 (0.97–2.16)0.07
Coronary artery disease1.21 (0.85–1.72)0.28
History of CVEs1.54 (1.03–2.31)0.04
Peripheral artery disease1.34 (0.89–2.00)0.16
LVEF (%)1.00 (0.99–1.01)0.75
Use of OAC1.11 (0.75–1.66)0.60
Full modelAdjusted HR (95% CI)P-valueSimplified modelAdjusted HR (95% CI)P-value
LAA filling defects1.86 (1.2–2.84)0.004LAA filling defects1.93 (1.28–2.92)0.002
Age (years)1.01 (0.98–1.04)0.41STS PROM1.08 (1.05–1.12)<0.001
Gender (female)0.90 (0.65–1.26)0.55Hypertension0.58 (0.39–0.85)0.005
Body mass index (kg/cm2)1.01 (0.97–1.04)0.75History of CVEs1.61 (1.09–2.39)0.02
STS PROM1.07 (1.03–1.11)<0.001Atrial fibrillation/flutter1.56 (1.11–2.19)0.01
Hypertension0.54 (0.37–0.81)0.003
Diabetes mellitus1.10 (0.76–1.58)0.62
CKD (GFR < 60)1.13 (0.76–1.68)0.55
Atrial fibrillation/flutter1.45 (0.97–2.16)0.07
Coronary artery disease1.21 (0.85–1.72)0.28
History of CVEs1.54 (1.03–2.31)0.04
Peripheral artery disease1.34 (0.89–2.00)0.16
LVEF (%)1.00 (0.99–1.01)0.75
Use of OAC1.11 (0.75–1.66)0.60

Assumed mean or modal values for missing data, missing were: BMI n = 5, LVEF n = 27, renal failure n = 3.

A subgroup analysis according to the LAA filling defects pattern is provided in Supplementary data online, Table S4. At 1 year, the rate of the primary endpoint was numerically higher in the thrombus-like (27.8%) and the heterogeneous pattern (27.5%) than the horizontal (18.6%) and the HU-run-off pattern (16.2%). The rate of cardiovascular death was similar among the thrombus-like (19.0%), the heterogeneous (22.0%), and horizontal (17.3%) pattern, while the rate was numerically lower in the HU-run-off pattern (10.9%). The incidence of cerebrovascular events according to LAA filling defects pattern is illustrated in Figure 6. The incidence of disabling stroke was particularly high in the thrombus-like pattern (23%), and low in the horizontal pattern (1.2%). As compared with the normal LAA filling pattern, the rate of the primary endpoint was significantly higher in the thrombus-like (HR 3.57, 95% CI 1.57–8.08; P = 0.002), heterogeneous (HR 3.18, 95% CI 1.67–6.94; P < 0.001), and the horizontal pattern (HR 2.11, 95% CI 1.22–3.66; P = 0.008), but not in the HU-run-off pattern (HR 1.88, 95% CI 0.83–4.27; P = 0.13). The higher incidence of the primary endpoint was driven by both cardiovascular death (HR 2.81, 95% CI 1.03-7.63, P = 0.04) and disabling stroke (HR 8.60, 95% CI 3.40–21.72; P < 0.001) in the thrombus-like pattern. In the heterogeneous and the horizontal pattern, it was primarily driven by cardiovascular death (HR 3.26, 95% CI 1.59–6.70; P = 0.001 and HR 2.58, 95% CI 1.45–4.59; P = 0.001, respectively) (Supplementary data online, Table S5). In contrast, relationships between the HU ratio and the primary endpoint were not significant (Supplementary data online, Figure S2).

Incidence of cerebrovascular events at 1 year after TAVI according to LAA filling defects pattern.
Figure 6

Incidence of cerebrovascular events at 1 year after TAVI according to LAA filling defects pattern.

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Discussion

The main findings of our study are summarized as follows: (i) LAA filling defects as detected by MDCT were found in 11% of patients undergoing TAVI; (ii) LAA filling defects were associated with an increased risk of cardiovascular death and disabling stroke; (iii) There is a differential risk according to the pattern of LAA filling defects with the highest stroke risk in patients with a thrombus-like pattern and the lowest risk in patients with a horizontal pattern.

Atrial fibrillation has been identified as an important risk factor of stroke and death in patients undergoing TAVI.2,3 Several studies suggested that the increased risk of stroke was primarily mediated by the presence of blood stagnation or thrombus in the LAA as assessed by TOE.4,12 Recently, a single case of LAAT embolization during TAVI has been reported.13 However, to date, LAA filling defects on MDCT, suggesting the presence of thrombus or blood stagnation in the LAA, have not been well studied with regards to its impact on stroke or death.6 In the present study, LAA filling defects on pre-procedural MDCT in patients undergoing TAVI were associated with a 2.5-fold and a 2.2-fold increase in the risk of death and disabling stroke, respectively, at 1-year following TAVI. As opposed to death which appears to occur consistently across 1 year, stroke events mainly occurred early after TAVI. This finding may have important implications for clinical practice. Given the clinical impact on outcomes following TAVI, LAA contrast-filling should be routinely evaluated by pre-procedural MDCT. If LAA filling defects are detected, further evaluation by TOE and a tailored antithrombotic strategy may be warranted. Continuation of oral anticoagulation during TAVI has been shown to be safe and effective in selected patients.14 In addition, cerebroembolic protection during the procedure may be used in patients with suitable anatomy.15 Alternatively, LAA closure may be safe and effective in patients with LAA filling defects and the absence of LAAT.16 Furthermore, Hioki et al.17 documented elimination of LAA filling defects following catheter ablation of atrial fibrillation along with continuation of oral anticoagulants in a single-centre experience.

Intriguingly, LAA filling defects were detected not only in patients with atrial fibrillation but also in patients without atrial fibrillation; and the impact on outcomes was accentuated in those without atrial fibrillation. As there is currently no recommendation on the use of oral anticoagulants for the management of LAA filling defects in the absence of atrial fibrillation, about 20% of patients with LAA filling defects were discharged without oral anticoagulants and had particularly high rates of adverse outcomes in the present study. Although it remains unclear at this stage whether the presence of LAA filling defects represents a marker for undiagnosed occult atrial fibrillation or indices hemodynamic abnormalities due to left ventricular/atrial dysfunction, tailored anti-thrombotic management using oral anticoagulants may be investigated in future studies. Additional screening for atrial fibrillation using Holter monitors or implantable loop recorders may also be considered.

MDCT is considered a valuable alternative to TOE for the detection of LAAT.18 A meta-analysis of 19 studies including 2955 patients evaluating the diagnostic performance of cardiac CT compared with TOE suggested a high diagnostic accuracy of CT in the detection of LAAT in patients with atrial fibrillation or history of stroke.19 Among the included studies, the mean sensitivity and specificity were 96% and 92%, respectively, with a positive predictive value of 41% and a negative predictive value of 99%. A recent study in a TAVI population demonstrated similar sensitivity and specificity of 100% and 98%, respectively, with a positive predictive value of 75% and a negative predictive value of 100%.5 The major disadvantage of MDCT as compared to TOE in the detection of LAAT is the high false-positive rate; however, false positives may indicate the presence of blood stagnation in the LAA along a continuous spectrum. Differences in patterns of appearances and HU ratios have been suggested to improve the diagnostic ability of MDCT.8,20,21 Feuchtner et al.8 reported characteristic imaging features suggesting incomplete filling of the LAA among false-positive cases, such as heterogeneous, horizontal, and HU-run-off patterns. In the present study, we utilized these patterns for the classification of LAA filling defects, and also evaluated the CT densities in HU.

Interestingly, a subgroup analysis according to the visual appearance of LAA filling defects indicated that the thrombus-like pattern was associated with the highest risk of stroke, while the other three characteristic patterns conferred a substantially lower risk. In particular, the horizontal pattern, the most common appearance of LAA filling defects, was less likely to be associated with stroke. Nevertheless, the heterogeneous and horizontal pattern conferred a significantly higher risk and the HU-run-off pattern conferred a numerically higher risk of the composite endpoint of cardiovascular death or disabling stroke compared to normal LAA filling, which was primarily driven by the higher incidence of cardiovascular death. These findings suggest that these cases may reflect ‘false positives’ in terms of LAA thrombus but indicate a gradient of delayed LAA filling on a continuous spectrum due to impaired cardiac performance or the morphological variance of the LAA.8 Further research is needed to investigate the clinical implications and potential mechanisms of these sub-types of LAA filling defects. Although the CT densities of LAA filling defects and HU ratio were lower in the thrombus-like pattern, they were also lower in the horizontal pattern, which is less likely to be associated with stroke risk. While CT densities as assessed by HU have been widely used for the detection of LAAT8,20,21 or for the evaluation of LAA patency after LAA closure,22 our data do not support their use in the prediction of clinical outcomes in patients undergoing TAVI.

Study limitations

This is the largest study, in which LAA filling defects were meticulously assessed in a core laboratory, and the first study to demonstrate the clinical impact of LAA filling defects on death and stroke in consecutive patients from a prospective registry with independent event adjudication. However, the reported findings need to be interpreted in light of several limitations. First, only 78% of all patients undergoing TAVI at our institution could be included in the present analysis due to the absence of MDCT or poor image quality. Second, while this is the largest cohort to explore the impact of LAA filling defects on clinical outcomes, numbers per sub-type of LAA filling defects pattern were small and need to be interpreted with caution. Although the assessment of LAA filling defects on MDCT has been well validated previously,5,8,19 the qualitative nature of the sub-type assessment may be subject to inter/intra-observer variability and needs to be further validated in future studies. Third, a delayed-phase MDCT protocol, which has been suggested to improve the diagnostic accuracy of LAAT,5 has not been routinely performed at our institution in accordance with current recommendations by the consensus of the Society of Cardiovascular Computed Tomography.23 Future studies are needed to define whether an additional delayed-phase scan refines risk stratification and improves patient management. And finally, the studied population in the present analysis was limited to very elderly patients (mean age >80 years) undergoing TAVI; the results are hence not generalizable to other populations.

Conclusion

LAA filling defects were found in one out of ten patients undergoing TAVI and were associated with a two-fold increased risk of cardiovascular death or disabling stroke following TAVI. Further research is needed to explore the importance of different patterns of LAA filling defects on clinical outcomes and whether this finding should guide subsequent thromboembolic preventive strategies in patients without previously known atrial fibrillation.

Supplementary data

Supplementary data are available at European Heart Journal - Cardiovascular Imaging online.

Acknowledgements

The data underlying this article were provided by CTU, University of Bern. T.P., T.O., and D.H. had full access to all the data in the study with permission of CTU, University of Bern, and take responsibility for the integrity of the data and the accuracy of the data analysis.

Data Availability

The data underlying this article were provided by CTU, University of Bern, by permission. Data will be shared on request to the corresponding author with permission of CTU, University of Bern.

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Author notes

Conflict of interest: S.W. reports research and educational grants to the institution from Abbott, Amgen, BMS, Bayer, Boston Scientific, Biotronik, Cardinal Health, CardioValve, CSL Behring, Daiichi Sankyo, Edwards Lifesciences, Johnson&Johnson, Medtronic, Querbet, Polares, Sanofi, Terumo, Sinomed. Stephan Windecker serves as unpaid member of the steering/executive group of trials funded by Abbott, Abiomed, Amgen, BMS, Boston Scientific, Biotronik, Cardiovalve, Edwards Lifesciences, MedAlliance, Medtronic, Novartis, Polares, Sinomed, V-Wave and Xeltis, but has not received personal payments by pharmaceutical companies or device manufacturers. He is also member of the steering/executive committee group of several investigated-initiated trials that receive funding by industry without impact on his personal remuneration. S.W. is an unpaid member of the Pfizer Research Award selection committee in Switzerland. T.P. reports research grants to the institiution from Boston Scientific, Biotronik, and Edwards Lifesciences, personal fees from Biotronik, Boston Scientific, and HighLife SAS; T.P. is a proctor for Boston Scientific and Medtronic. M.V. reports research grants to the institution from Terumo, and personal fees from Astra Zeneca, Alvimdeica/CID, Abbot Vascular, Daiichi Sankyo, Opsens, Bayer, CoreFLOW, IDORSIA PHARMACEUTICALS LTD, Universität Basel Dpt. Kinische Forschung, Vifor, Bristol Myers Squib SA, iVascular Medscape. S.S. has received research grants to the institution from Edwards Lifesciences, Medtronic, Abbott Vascular and Boston Scientific, speaker fees from Boston Scientific and consultant fees from BTG (former British Technology Group) and Teleflex. F.P. has received travel expenses from Edwards Lifesciences, Abbott Medical, Polares Medical. T.O. reports speaker fees from Abbott. D.H. reports and with CTU Bern, University of Bern, which has a staff policy of not accepting honoraria or consultancy fees. However, CTU Bern is involved in design, conduct, or analysis of clinical studies funded by not-for-profit and for-profit organizations. In particular, pharmaceutical and medical device companies provide direct funding to some of these studies. For an up-to-date list of CTU Bern’s conflicts of interest see http://www.ctu.unibe.ch/research/declaration_of_interest/index_eng.html. All other authors have no relationships relevant to the contents of this article to disclose.

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