Keywords
cardiac events - computed tomographic imaging - aortic and arterial diseases - atrial
fibrillation - oral anticoagulant treatment
Introduction
Vitamin K antagonists (VKAs) and non–vitamin K antagonist oral anticoagulants (NOACs)
are widely prescribed drugs for prophylaxis and treatment of thromboembolic events.
Although VKAs are proven to be effective in preventing thromboembolic events, their
potential adverse effect in promoting soft-tissue calcification has not been taken
into account in clinical management. VKAs exert their antithrombotic effect through
interference with vitamin K metabolism, which is not limited to vitamin K–dependent
coagulation factors, but also all vitamin K–dependent proteins, including those involved
in calcification.[1] Clinical studies confirm the association between VKA and vascular calcification.[2]
[3]
[4] Since vascular calcification is known to be a marker of increased cardiovascular
morbidity and mortality,[5] VKA-induced calcification has become nonnegligible—certainly in initially low- to
intermediate-risk populations. This holds even more since current guidelines recommend
oral anticoagulant (OAC) treatment even in low-risk atrial fibrillation (AF) patients
with only one stroke risk factor.[6]
NOACs are a modern alternative to VKA since trials proved NOACs to be noninferior
to VKA treatment for several indications.[7] NOACs exert their anticoagulant effect by direct inhibition of either factor IIa
or factor Xa in the coagulation cascade. Thus, NOACs are hypothesized to lack the
detrimental effect on calcification.[1]
[8]
Therefore, the purpose of this study was to investigate the contribution of VKA treatment
and NOAC treatment to vascular calcification of the aortic valve and the aorta in
patients with AF.[1]
[2]
Methods
Study Population
In this cross-sectional observational study, 236 patients with AF without a history
of major adverse cardiac and cerebrovascular events (cardiac arrest, acute coronary
syndrome, revascularization, or stroke) were included. Patients were divided in three
groups according to type of anticoagulation: no oral anticoagulation, VKA (acenocoumarol;
scan date: 2007–2010) or NOAC (rivaroxaban [n = 59], and dabigatran [n = 11], or apixaban [n = 9]; scan date: 2011–2016). Part of this population (non-anticoagulant group and
VKA group) has been described previously.[9] In short, patients with paroxysmal AF undergoing a cardiac multislice computed tomography
(MSCT) scan were included and the PROCAM risk score was determined. Patients with
significant and untreated cardiovascular disease (CVD) including (untreated) hypertension,
diabetes mellitus or hypercholesteremia, coronary artery disease, chronic kidney disease,
or heart failure were not included. For the purpose of this study, a similar strategy
was used to include CT scans of patients with NOAC treatment. Additionally, patients
in whom OAC therapy was initiated with VKA and changed to NOAC over the years were
excluded. All patients underwent MSCT either for workup before an electrophysiological
ablation or for general checkup for coronary artery disease and were in sinus rhythm
during examination. Clinical information was obtained from the electronic hospital
charts and the absolute 10-year risk of an acute coronary event (fatal of nonfatal
myocardial infarction or acute coronary death) was determined using the PROCAM risk
score.[10] This study was approved by the local institutional review board.
Data Acquisition and Analysis of Cardiac Multislice Computed Tomography
A non–contrast-enhanced coronary calcium scan was performed in all patients as described
previously.[9] CT scans were performed using a Philips Brilliance 64-slice MSCT scanner (Philips
Healthcare, Best, the Netherlands), second-generation dual-source CT scanner (Somatom
Definition Flash 2*128-slice; Siemens Healthineers, Forchheim, Germany), or third-generation
dual-source CT scanner (Somatom Definition Force 2*192; Siemens Healthineers). CT
scans of Philips Brilliance MSCT scanner were analyzed with dedicated EBW Heartbeat
CS software (Philips Healthcare). CT scans of the Siemens Somatom Definition Flash
or Force were assessed using source images on a dedicated workstation (Syngo.via;
Siemens Healthineers). For quantitative assessment of aortic valve and ascending and
descending aorta calcification, the Agatston score was determined using a 3-mm CT
slice thickness and a detection threshold of ≥130 HU involving ≥1 mm2 area/lesion (3 pixels).[11] The presence of calcification of the ascending aorta calcification (AsAC), descending
aorta calcification (DAC), and aortic valve calcification (AVC) was defined as Agatston
score greater than 0. Calcium localized above the origin of the right coronary artery
to the end of scan range, or up to the origin of the brachiocephalic artery, was considered
to be in the ascending aorta. Calcium present distal from the origin of the left subclavian
artery up to the diaphragm was considered to be localized in the descending aorta.
The Agatston score of each segment was calculated separately by two independent observers,
both blinded to medical data. In case of ambiguity, consensus was reached by discussion.
Echocardiography
An independent observer performed the echocardiography while subjects were lying in
the left lateral decubitus position. Standard two-dimensional transthoracic echocardiography
was performed, including M-mode, and Doppler echocardiography (Sonos 5500 and IE33;
Philips Medical Systems, Andover, Massachusetts, United States) according to the guidelines
of the European Association of Echocardiography.[12]
Statistical Analyses
Statistical analyses were performed using SPSS version 22 (IBM Corp, Armonk, New York,
United States). Normally distributed continuous variables are expressed as mean ± standard
deviation (SD) and compared using independent samples t-testing. Non-normally distributed continuous variables are expressed as median (interquartile
range [IQR]) and compared using the Mann–Whitney U-test. Categorical variables are expressed as absolute numbers and percentages and
tested using the χ
2 test or Fisher's exact test.
Patients were stratified according to type of treatment (non-anticoagulant, VKA, or
NOAC), the effect on the primary outcome, and the presence of calcification in the
ascending and descending aorta, and the aortic valve between the groups was investigated
using propensity scores ([Supplementary Fig. S1]). Since patients were not randomly assigned to type of treatment, we adjusted for
factors favoring non-anticoagulant, VKA, or NOAC prescription using propensity score
to reduce the selection bias and see the genuine effect of therapy on the primary
outcome. Groups were compared in a pairwise manner,[13] and for every pair, two analyses were performed as previously described. First,
variables (mentioned in [Table 1]) associated with VKA or NOAC treatment were identified by univariable logistic regression
(retention level set at 0.1). Subsequently, propensity scores of the variables showing
a significant relation with prescription of VKA or NOAC were calculated for each patient
and integrated in the logistic regression models as a covariate with the presence
of calcification in the ascending aorta, descending aorta, and the aortic valve as
outcome variables. Second, a propensity score–matched analysis was performed for every
pair, in which patients were propensity score matched to patients in the treatment
group they were to be compared with, using the Greedy matching strategy.[13]
[14] Propensity scores were matched to the closest propensity score of a patient in the
other treatment arm with a maximum difference of 5%. Matching was repeated until all
patients were matched, or until the propensity scores differed greater than 5% between
arms. The χ2 test was performed to assess the differences in the presence of AsAC, DAC, and AVC.
Table 1
Baseline characteristics of the total population
|
Total population (n = 236)
|
Non-anticoagulant (n = 86)
|
VKA (n = 71)
|
NOAC (n = 79)
|
|
Demographics
|
|
Age (y)
|
58.3 ± 9.2
|
55.8 ± 9.1
|
57.9 ± 9.0
|
61.5 ± 8.5
|
|
Male sex
|
159 (67.4)
|
53 (61.6)
|
57 (80.3)
|
49 (62.0)
|
|
BMI (kg/m2)
|
27.1 ± 3.6
|
26.6 ± 3.3
|
27.5 ± 3.2
|
27.2 ± 4.2
|
|
Smoking
|
27 (11.4)
|
11 (12.8)
|
8 (11.3)
|
8 (10.1)
|
|
Positive family history (AMI)
|
33 (14.0)
|
9 (10.5)
|
7 (9.9)
|
17 (21.5)
|
|
Systolic blood pressure (mm Hg)
|
128.2 ± 12.9
|
125.5 ± 9.9
|
124.5 ± 10.7
|
134.4 ± 15.1
|
|
Fasting blood glucose (mmol/L)
|
5.44 ± 0.52
|
5.43 ± 0.43
|
5.31 ± 0.54
|
5.58 ± 0.56
|
|
Cholesterol (mmol/L)
|
5.40 ± 0.96
|
5.44 ± 0.90
|
5.47 ± 1.14
|
5.28 ± 0.83
|
|
Triglycerides (mmol/L)
|
1.68 ± 0.92
|
1.56 ± 0.82
|
1.79 ± 1.13
|
1.70 ± 0.78
|
|
LDL (mmol/L)
|
3.41 ± 0.83
|
3.55 ± 0.73
|
3.52 ± 0.99
|
3.16 ± 0.74
|
|
HDL (mmol/L)
|
1.27 ± 0.35
|
1.20 ± 0.28
|
1.21 ± 0.41
|
1.41 ± 0.34
|
|
Creatinine (μmol/L)
|
86.7 ± 13.9
|
86.2 ± 14.2
|
88.9 ± 12.6
|
85.6 ± 14.5
|
|
PROCAM risk score (%)
|
7.0 [7.0]
|
5.7 [7.6]
|
7.0 [9.3]
|
7.0 [6.0]
|
|
CHA2DS2-VASc score
|
1.0 [1.0]
|
1.0 [1.0]
|
1.0 [1.0]
|
1.0 [1.0]
|
|
Anticoagulation duration (wk)
|
NA
|
NA
|
122 [158]
|
16 [36]
|
|
AF duration (mo)
|
25 [70]
|
26 [72]
|
42 [71]
|
8 [24]
|
|
Medication
|
|
Rhythm control
|
146 (61.9)
|
51 (59.3)
|
51 (71.8)
|
44 (55.7)
|
|
Rate control
|
120 (50.8)
|
41 (47.7)
|
40 (56.3)
|
39 (49.4)
|
|
ACE inhibitors
|
32 (13.6)
|
9 (10.5)
|
11 (15.5)
|
12 (15.2)
|
|
Angiotensin receptor blockers
|
54 (22.9)
|
16 (18.6)
|
18 (25.4)
|
20 (25.3)
|
|
Diuretics
|
33 (14.0)
|
8 (9.3)
|
12 (16.9)
|
13 (16.5)
|
|
Statins
|
37 (15.7)
|
13 (15.1)
|
13 (18.3)
|
11 (13.9)
|
|
Echocardiography
|
|
LA dimension (mm)
|
41.1 ± 5.2
|
40.0 ± 5.1
|
42.5 ± 5.0
|
41.1 ± 5.2
|
|
LA volume (mL)
|
76.8 ± 23.6
|
69.5 ± 21.9
|
80.3 ± 21.6
|
81.9 ± 25.7
|
|
RA volume (mL)
|
60.8 ± 24.8
|
57.0 ± 18.5
|
62.2 ± 22.7
|
64.0 ± 32.5
|
|
IVS (mm)
|
8.6 ± 0.8
|
8.5 ± 0.8
|
8.7 ± 0.8
|
8.7 ± 0.8
|
|
PW (mm)
|
8.5 ± 0.8
|
8.5 ± 0.7
|
8.6 ± 0.8
|
8.5 ± 0.8
|
|
LVEF (%)
|
60.2 ± 6.0
|
60.9 ± 6.1
|
60.5 ± 6.5
|
59.1 ± 5.1
|
Abbreviations: ACE, angiotensin-converting enzyme; AF, atrial fibrillation; AMI, acute
myocardial infarction; BMI, body mass index; HDL, high-density lipoprotein; IVS, interventricular
septum; LA, left atrium; LDL, low-density lipoprotein; LVEF, left ventricular ejection
fraction; PW, posterior wall; RA, right atrium.
Notes: Continuous variables are expressed as mean ± SD or median [IQR] depending on
their distribution. Categorical variables are reported as n (%).
Fig. 1 (A) Presence of calcification in different segments in total population and according
to treatment type. (B) Distribution of calcification (Agatston scores) in the ascending aorta, descending
aorta, and aortic valve in the total population. (“*” indicates the number of values
>500). AsAC, ascending aortic calcification; DAC, descending aortic calcification;
AVC, aortic valve calcification; non-OAC, non-oral anticoagulant; VKA, vitamin K antagonist;
NOAC, non–vitamin K antagonist oral anticoagulant.
The Jonckheere–Terpstra test was performed to assess whether duration of VKA treatment
(in tertiles) was associated with the height of the total Agatston score in the VKA
treatment group. A similar analysis could not be performed in NOAC users, due to the
shorter duration of treatment in this group. Overall, statistical significance was
assumed for p < 0.05.
Results
Baseline Variables
Mean age ( ± SD) of the total population was 58 ± 9 years, 67% (n = 159) were male and the median (IQR) CHA2DS2-VASc score was 1.0. Indications for MSCT were workup for ablation (51.5%) and general
checkup for coronary artery disease. Further baseline characteristics are shown in
[Table 1]. AsAC, DAC, or AVC was present in 81 (34.3%), 109 (46.2%), and 88 (37.3%) patients,
respectively ([Fig. 1A], [B] and [Supplementary Fig. S2]). A total of 47 (19.9%) patients showed calcification of both the aortic segments
and the aortic valve. Of the total study population, 86 patients (36.4%) were in the
non-anticoagulant group, 71 (30.1%) in the VKA group, and 79 (33.5%) in the NOAC group.
Median durations of VKA and NOAC treatments were 122 (IQR: 51–209) and 16 (IQR: 6–42)
weeks, respectively.
Fig. 2 AsAC, DAC, and AVC in propensity score–adjusted regression analyses (odds ratio [95%
CI]). (Panel A) Non-anticoagulation (reference) versus VKA. (Panel B) Non-anticoagulation (reference) versus NOAC. (Panel C) NOAC (reference) versus VKA. AsAC, ascending aortic calcification; DAC, descending
aortic calcification; AVC, aortic valve calcification; VKA, vitamin K antagonist;
NOAC, non–vitamin K antagonist oral anticoagulant.
Identification of Confounders for VKA or Direct Oral Anticoagulant Treatment
Patients on VKA treatment were more likely to be male and treated with rhythm control
medication than non-anticoagulant patients. Moreover, they were more likely to have
a higher body mass index and larger left atrial diameters. Compared with the non-anticoagulant
or VKA group, NOAC users were older, more likely to have higher systolic blood pressure,
and their medical history with AF and thus anticoagulant treatment duration was shorter;
however, they had a comparable left atrial volume to the VKA group. Additionally,
they had a more favorable low-density lipoprotein and high-density lipoprotein cholesterol
profile. In pairwise comparison between NOAC and VKA users, NOAC users were more likely
to be of female sex and had slightly higher plasma glucose levels ([Supplementary Table S1]).
Calcification Differences between Types of Anticoagulation
Distribution of prevalence of calcification of all segments of the three groups is
displayed in [Fig. 1].
Regression analyses, adjusted for the propensity scores to correct for the identified
confounders, revealed that patients in the VKA treatment group had significantly more
AsAC and DAC when compared with the non-anticoagulation group (AsAC: odds ratio [OR]
2.31, 95% confidence interval [CI] 1.16–4.59, p = 0.017; DAC: OR 2.38, 95% CI 1.22–4.67, p = 0.012) and showed a trend toward a higher calcium score of the aortic valve (AVC:
OR 1.92, 95% CI 0.98–3.80, p = 0.059; [Fig. 2A]). AsAC, DAC, and AVC were not significantly different between the non-anticoagulation
and NOAC groups (AsAC: OR 0.51, 95% CI 0.21–1.21, p = 0.127; DAC: OR 0.80, 95% CI 0.36–1.76, p = 0.577; AVC: OR 0.62, 95% CI 0.27–1.40, p = 0.248, respectively; [Fig. 2B]). Occurrence of DAC and AVC was significantly higher in the VKA group when compared
with the NOAC group (DAC: OR 3.60, 95% CI 1.18–10.97, p = 0.025; AVC: OR 3.26, 95% CI 1.09–9.70, p = 0.034). AsAC was higher in the VKA treatment group as compared with the NOAC group,
although a significant difference was not reached (AsAC: OR 2.39, 95% CI 0.82–6.92,
p = 0.109; [Fig. 2C]).
Calcification Differences in the Propensity Score–Matched Population
A total of 178 patients were propensity score matched in three pairwise comparisons
according to treatment type. For comparison between non-anticoagulation and the VKA
group, 118 patients were matched (59 in each group). These numbers were 32 and 28
(16 and 14 per group) for the non-anticoagulation/NOAC and the NOAC/VKA comparisons,
respectively. After the matching procedure, clinical conditions and echocardiographic
measurements were identical ([Supplementary Table S2]).
When comparing the presence of calcification between the propensity score–matched
groups of non-anticoagulation and VKA, the presence of DAC remained significantly
higher in the VKA-treated group (n = 23 [39.0%] vs n = 34 [57.6%], p = 0.043), while AsAC showed a trend toward a higher presence (n = 18 [30.5%] vs. n = 28 [47.5%], p = 0.059). AVC was not significantly different between the two groups (n = 24 [40.7%] vs. n = 29 [49.2%] p = 0.355; [Fig. 3A]).
Fig. 3 AsAC, DAC, and AVC per treatment group after propensity score matching. (A) Propensity score–matched cohort non-anticoagulation/VKA. (B) Propensity score–matched cohort non-anticoagulation/NOAC. (C) Propensity score–matched cohort NOAC/VKA. Statistical testing using chi-square.
AsAC, ascending aortic calcification; DAC, descending aortic calcification; AVC, aortic
valve calcification; non-OAC, non-anticoagulant; VKA, vitamin K antagonist; NOAC,
non–vitamin K antagonist oral anticoagulant.
The non-anticoagulation/NOAC-matched cohort did not reveal significant differences
of AsAC, DAC, and AVC (n = 7 [43.8%] vs. n = 4 [25.0%], p = 0.264; n = 9 [56.3%] vs. n = 5 [31.3], p = 0.154; n = 8 [50.0%] vs. n = 5 [31.3%], p = 0.280; [Fig. 3B]). Less calcification in AsAC and DAC was seen in the NOAC group, although statistical
significance was not reached (p = 0.225 and p = 0.127); yet AVC was statistically significantly different between these groups
(n = 3 [21.4%] vs. n = 10 [71.4%], p = 0.008; [Fig. 3C]).
Vitamin K Antagonist Duration and Calcification
Duration of treatment with VKA differed between patients. The Jonckheere–Terpstra
test revealed a statistically significant trend between the extent of total vascular
calcification and increased duration of VKA treatment (p = 0.034). The rise in calcification levels and VKA duration is illustrated in [Fig. 4].
Fig. 4 Vascular calcium score categories (tertiles) in patients with different treatment
duration of vitamin K antagonist (VKA). Statistical testing using Jonckheere–Terpstra
test.
Discussion
This study investigated the effect of anticoagulant treatment with VKAs and NOACs
on vascular calcification as compared with patients with AF not treated with oral
anticoagulation. The main finding of this study is that treatment with VKA is associated
with a higher prevalence of calcification of the thoracic aorta when compared with
patients without oral anticoagulation or NOAC treatment, whereas a difference in calcification
between the NOAC and group without oral anticoagulation was not observed.
Vitamin K Antagonists and Vascular Calcification
Several studies describing populations with variable CVD profiles reported an association
between vascular and valvular calcification and VKA use.[2]
[3]
[4] Additionally, two studies considering relatively low-risk populations reported an
association between femoral artery calcification and coronary artery calcification
and VKA treatment.[9]
[15] Using propensity-matched analyses, we provide a funded direction to causality and
show that in patients with similar risk profiles, those treated with VKA have more
calcification of systemic arteries and the aortic valve in comparison to patients
not treated with VKA. With that, our results are in accordance with previous data
and extend knowledge, derived from these studies involving patients with different
risk profiles, all treated with VKA. Although former studies showed controversial
results,[2]
[16] we observed a trend in the duration of VKA treatment toward increased vascular calcification
in the present population, hinting toward a direct calcification-inducing effect of
VKA.
The Mechanism Connecting Vitamin K Antagonist and Calcification
VKAs are established in the prevention of thromboembolic complications and exert their
anticoagulant effect by inhibition of the activation of vitamin K–dependent coagulation
factors II, VII, IX, and X. Bleeding is a major adverse effect of VKA and has been
extensively described in literature. However, the calcification-induction potential
of VKAs is not considered in its prescription in daily clinical practice. This effect
on calcification is caused by the inhibition of matrix-γ-carboxyglutamic acid (Gla)
protein (MGP), a vitamin K–dependent protein synthesized by vascular smooth muscle
cells (VSMC).[17] The function of MGP as an inhibitor of soft-tissue calcification was shown in MGP-deficient
mice which developed extensive arterial calcification and died within 2 months due
to aortic rupture.[18] The effect of VKA on calcification was demonstrated in experimental animal models
which showed similar development of calcification in vascular and aortic valve tissue
as in MGP knockout animals.[19] The inhibition of MGP by VKA results in decreased calcium binding and inhibition
of calcium crystals formation and bone morphogenetic protein action.[18]
[20]
[21] The loss of inhibitory function is furthermore caused by a relative shortage of
vitamin K due to upregulation of MGP in areas with calcification, resulting in a high
ratio of uncarboxylated versus carboxylated MGP. The last phenomenon is clinically
associated with an increased risk for arterial and coronary calcification.[22]
[23]
[24]
VKA versus NOAC for Patients with Atrial Fibrillation
Aortic calcification is considered a subclinical marker of atherosclerosis, like coronary
artery calcification, sharing risk factors with the latter.[25] The prognostic value of cardiovascular calcification has clearly been demonstrated
in several patient populations with CVD, showing an increased risk of future events
with increasing calcification.[26]
[27] The negative pharmacological characteristics and adverse events associated with
the use of VKA opened the market for a new generation of anticoagulants (NOACs).[1] NOACs exert their anticoagulant effect by direct inhibition of factors IIa or Xa,
and thus NOACs do not interfere with vitamin K–dependent proteins such as MGP.[17] In our study, we found no difference between the group of patients treated with
NOACs as compared with those without oral anticoagulation. Furthermore, although treatment
duration has to be taken into account, we found less calcification in the NOAC group
in comparison to the VKA group. Thereby, although preliminary, we provide evidence
that NOACs lack the calcification-induction effect of VKAs. The effect of both VKA
and NOACs on both valvular and vascular calcification (including coronary artery calcification)
is currently investigated in randomized controlled trials considering populations
with different cardiovascular disease profiles.[28]
Next to the suggested absence of this calcification inducing effect, direct beneficial
effects of NOACs on attenuation of atherosclerosis and plaque stability have been
suggested in animal models,[29] as NOACs inhibit PAR-receptor function through inhibition of factors IIa or Xa.
Exemplary for this is that the COMPASS trial, investigating whether rivaroxaban alone
or added to aspirin led to less cardiovascular events in comparison to aspirin alone,
was halted after the interim analysis revealed superiority of the combined rivaroxaban
plus aspirin in comparison to aspirin alone.[30] As AF is generally associated with an increased cardiovascular risk profile, this
effect of NOACs can be expected to be of particular value in AF patients.
Overall, growing insight in the presence/absence of calcification-induction of different
OACs and their effect on atherosclerosis holds potential to provide important implications
to aid clinicians in their choice for anticoagulant treatment type, especially in
patients with lifelong indication for OAC, such as patients with AF.
Strengths and Limitations
Strengths and Limitations
Our study creates the opportunity to assess the true effect of the anticoagulation
type in patients with a comparable cardiovascular profile by excluding several potential
variables that could have influenced this effect, providing a funded direction toward
a causal relationship. We believe that our results are of additive value due to the
method of analyses using propensity score matching. Although the current study provides
important insight, some caution must be considered with the interpretation. First,
the sample size of the study resulted in relatively small propensity-matched arms
of non-anticoagulation/NOAC and NOAC/VKA. Trials with a higher number of patients
should be performed to overcome issues regarding the power in this study. Second,
we tried to circumvent limitations generally involved in studies with a retrospective
nature and a cross-sectional design. However, the design of the current study does
not allow correcting for unmeasured confounders, whereby residual confounding could
persist. Furthermore, levels of calcification before initiation of anticoagulation
are unknown, and may have differed between patients. Also, the overall quality of
anticoagulation control for patients treated with VKA could not be determined reliably.
At last, the shorter duration of NOAC treatment in the current study has to be taken
into account. Therefore, this result has a rather basic nature regarding the true
(absent) effect of NOACs on calcification. Extrapolation of these results to a broader
patient population should be done with caution. Studies on long-term use of NOAC are
necessary to confirm these findings and to provide valuable additional information
in the determination of a true “absent” effect of NOACs on calcification.
Conclusion
Vascular calcification is known to be a marker of increased cardiovascular morbidity
and mortality, making it nonnegligible, certainly in initially low-risk populations.
All studies performed so far suggest vascular calcification, but could not define
true causality between VKA and aortic and valvular calcification due to their design.
Yet in this study, we show that VKA contributes to the presence of vascular calcification,
which is not observed in NOAC. To address the question whether VKAs cause vascular
calcification and NOACs do not, randomized controlled trials are on their way.
