Version of Record: https://www.sciencedirect.

com/science/article/pii/S0049384821005090
Manuscript_4ef2c3972eb68c3ba409d69b637eddb8

Title page

Title: Management of acute venous thromboembolism in patients taking antiplatelet

therapy.

Short title: Acute venous thromboembolism and antiplatelet use

Marie Giraud 1, Judith Catella 1, Lucile Cognet 2, Hélène Helfer 2, Sandrine Accassat 1,3, Céline
Chapelle4, Patrick Mismetti 1, 3,5, Silvy Laporte 4,5, Isabelle Mahé 2, Laurent Bertoletti 1, 3,5

Affiliations

1. Service de Médecine Vasculaire et Thérapeutique, Centre Hospitalier Universitaire de

Saint-Etienne - Saint-Etienne (France)

2. Université de Paris, Service de Médecine Interne, Hôpital Louis Mourier, AP-HP- Colombes
(France), Inserm UMR_S1140, Innovations thérapeutiques en hémostase, Paris, France
3. INSERM CIC 1408, Centre Hospitalier Universitaire de Saint-Etienne - Saint-Etienne
(France)

4. Unité de Recherche Clinique Innovation Pharmacologie, Centre Hospitalier Universitaire

de Saint-Etienne – Saint-Etienne France

5. INSERM UMR 1059 SAINBIOSE, Université Jean-Monnet - Saint-Etienne (France).

Corresponding author:

Laurent BERTOLETTI, laurent.bertoletti@gmail.com

Service de Médecine Vasculaire et Thérapeutique, CHU de St-Etienne, F-42055, Saint-

Etienne, France. +33477827771; fax: +33477820482

1
© 2021 published by Elsevier. This manuscript is made available under the Elsevier user license
https://www.elsevier.com/open-access/userlicense/1.0/
ABSTRACT (249 words)

Background: Concomitant anticoagulant and antiplatelet therapy increases bleeding risk, but
most data are derived from patients with atrial fibrillation. Patients with venous
thromboembolism (VTE) may differ.

Objective: To study the management of patients diagnosed with acute VTE while receiving
antiplatelet treatment. The primary outcome was the number of patients discharged with
concomitant therapy. Secondary outcomes were clinically relevant bleeding, cardiovascular
events, recurrent VTE and death during follow-up, according to discharge therapy.

Methods: We performed a post-hoc analysis of patients included in two prospective

registries, sharing the same case report form, from 2007 to 2017.

Results: Among the 1694 identified patients, 254 (15.0%) were receiving antiplatelet
treatment at VTE diagnosis, of whom 61 (24.0%) were discharged with concomitant
anticoagulant and antiplatelet therapy. In multivariable analysis, age ≥ 80 years-old and the
use of Direct Oral Anticoagulants for VTE therapy were associated with the decision to stop
the antiplatelet, while having dual anti-platelet therapy at baseline, a history of coronaropathy
or peripheral arterial disease were associated with concomitant anticoagulant and
antiplatelet therapy. The decision to stop antiplatelet was associated with a non-significant
46% decrease in the risk of bleeding (OR 0.54 (0.16; 1.78)), and a non-significant 68%
increase in the risk of cardiovascular events (OR 1.68 (0.44; 6.46)).

Conclusion: At acute VTE diagnosis, over 15% of patients were receiving antiplatelet agents,
of whom 24% were discharged with concomitant anticoagulant and antiplatelet therapy.
This therapeutic decision may be associated with a lower risk of cardiovascular events, but
an increased risk of bleeding.

Keywords:
Venous Thrombosis
Platelet Aggregation Inhibitors
Hemorrhage
Anticoagulants
Aspirin

2
INTRODUCTION

Venous thromboembolism (VTE), comprising deep-vein thrombosis (DVT) and pulmonary

embolism (PE), is a commonly diagnosed condition with significant morbidity and mortality
[1]. Current guidelines recommend treating patients with anticoagulant therapy for at least
three months, extended anticoagulant therapy being proposed to more and more patients
[2]. While extended anticoagulant therapy effectively reduces the risk of recurrent VTE, it
carries a risk of bleeding [1]. This risk doubles in patients aged 65 years or more,
representing approximately two-thirds of patients with VTE [1]. Furthermore, VTE commonly
coexists with comorbid conditions such as atherosclerotic vascular diseases [2]. Thus, a
significant proportion of patients (ranging from 7 to 35%) experience a VTE event while
under antiplatelet therapy because of prior myocardial infarction, stroke or other arterial
events [3–6]. For these patients, few data are available to guide the most appropriate
management strategy between discontinuing antiplatelet therapy or continuing this (in
combination with anticoagulation therapy).

Most of the available data on the concomitant use of anticoagulant and antiplatelet therapy
derive from studies in patients with atrial fibrillation (AF). In this population, combined use
of anticoagulants and antiplatelet agents is associated with an increased risk of major
bleeding [7]. A Danish study found that dual warfarin-clopidogrel therapy and triple
warfarin-clopidogrel-aspirin therapy carried a more than 3-fold higher risk for both fatal and
non-fatal bleeding than warfarin monotherapy in patients with AF and myocardial infarction
[8]. The 2016 European Society of Cardiology guidelines therefore recommended reserving
combination therapy for patients with AF (or mechanical heart valves) who had recently
experienced an acute coronary syndrome [9].

Data concerning patients with VTE are scarce, and rather conflicting. In patients with acute
VTE, investigators from the RIETE registry (Registro Informatizado de Enfermedad
ThromboEmbolica) found that antiplatelet therapy was discontinued in 729 out of 1178
patients (62%) receiving antiplatelet drugs at the time of VTE diagnosis [10]. During follow-
up (median duration: 8 months), the rates of bleeding, recurrent VTE, ischemic events and
death were similar between the groups. Conversely, among prevalent elderly Swiss patients
who had completed at least 6 months of vitamin-K antagonist (VKA) therapy for VTE,
concomitant use of an antiplatelet agent was recognized as a risk factor for major bleeding
3
[1]. In a recent retrospective US cohort study of patients receiving anticoagulant therapy
with VKA for AF or VTE [6], more than a third were receiving concomitant aspirin therapy,
this association being associated with an increased risk of clinically relevant bleeding (major
bleeding and/or bleeding requiring hospitalization) after 1 year of follow-up.

Hence, many questions remain concerning patients with acute VTE, such as the proportion
and characteristics of patients in whom antiplatelet therapy is maintained concomitantly
with anticoagulation, or their outcome, compared to those in whom antiplatelet therapy
was discontinued.

The aim of this study was to analyze the proportion of patients taking antiplatelet therapy at
the time of VTE diagnosis, and to compare the treatment strategy adopted (concomitant
anticoagulant and antiplatelet therapy or discontinuation of antiplatelet therapy) according
to clinical characteristics in two tertiary vascular centers.

4
METHODS

Study design

We conducted a post-hoc analysis of all patients included prospectively in two local VTE
registries, sharing the same case report form. All patients were admitted for acute
objectively confirmed VTE between 01/01/2007 and 31/12/2017 in different departments of
Saint Etienne University Hospital and Louis Mourier Paris University Hospital. All patients
provided their consent to participate in the study according to local regulations. Data were
recorded on a computer-based case report form (declared to the French “Commission
Nationale de l’Informatique et des Libertés” [CNIL]). The study was approved by the local
ethical committee (Terre d’éthique, N° IRBN402018/CHUSTE). The primary objective was to
determine the proportion of patients who were discharged with concomitant anticoagulant
and antiplatelet therapy (the AC+APT group), compared to those in whom antiplatelet
therapy was discontinued (the AC group). Secondary objectives were to assess the initial
clinical characteristics of the patients and their outcomes according to the decision to
maintain or discontinue antiplatelet therapy. Patients were followed until the first outcome
or until the last news of the patient if no event occurred.

Study population

Among all the patients included in the registries, we identified those who were receiving
antiplatelet therapy at the time of VTE (PE and/or DVT) diagnosis and who were prescribed
anticoagulant treatment at curative dosage and who have been followed up for a minimum
of 3 months. DVT was defined as a thrombosis involving at least one deep vein, objectively
confirmed by compression ultrasound, including gray-scale or color-coded Doppler, or
ascending contrast venography. PE was objectively confirmed as follows: an intraluminal
filling defect in one or more segmental or proximal branches on spiral CT scan; or an
intraluminal filling defect or a sudden cutoff of vessels more than 2.5 mm in diameter on the
pulmonary angiogram; or a perfusion defect affecting at least 75% of a segment with a local
normal ventilation result on a high-probability ventilation/perfusion lung scan[11].

Outcomes

5
The outcomes analyzed were clinically relevant bleeding (CRB), cardiovascular events,
recurrent VTE and death during follow-up. CRB correspond to any major bleeding or clinically
relevant non-major bleeding. Major bleeding was defined according to International Society
on Thrombosis and Haemostasis criteria as overt bleeding that required a transfusion of two
or more units of blood, or occurred in a critical site (retroperitoneal, spinal, intracranial,
ocular, intra-articular, pericardial, or muscular with compartment syndrome) or led to death
[12]. Clinically relevant non-major bleeding was defined according to International Society
on Thrombosis and Haemostasis criteria as bleeding considered as non-major but
necessitating a medical or surgical intervention, including a change in antithrombotic
therapy, or leading to hospital admission [13]. Cardiovascular events were defined as
objectively confirmed myocardial infarction, ischemic stroke and lower limb ischemia.
Recurrent VTE was defined as a new episode of VTE or an increase in clot size confirmed by
objective tests.

Treatment and follow-up

Patients were managed according to the clinical practice of each hospital. The type, dose
and duration of anticoagulant and antiplatelet therapy were recorded. Patients were
followed in the anticoagulation clinic throughout the course of their anticoagulation therapy.
The last date of follow-up for the study corresponded to the time of the last news of the
patient, the time of the first event of interest, or the discontinuation of anticoagulant
therapy. We searched the medical records for ischemic events, bleeding complications or
recurrent VTE. In the case of such an outcome, we recorded the type and dose of
anticoagulant and/or antiplatelet agent at that moment and the changes, if any, made in
subsequent treatment (maintenance, discontinuation or switch of anticoagulant or
antiplatelet therapy or both).

Statistical analysis

The analyses were performed on all patients included, based on the data obtained up to the
last news of each patient, or up to occurrence of the first event of interest. Study population
characteristics are reported as means ± Standard Deviation (SD) for continuous
variables, and number and percentages for categorical variables. Univariate analyses were
performed to screen for potential confounding factors associated with the decision to stop

6
antiplatelet therapy using a logistic regression model. The predefined potential confounding
factors tested were: characteristics of patients (age ≥ 80 years-old, gender, body weight < 50
kg), treatment at inclusion (type of antiplatelet agent, type of anticoagulation), type of VTE
at inclusion, venous thrombosis history, bleeding risk factors (major bleeding < 2 months,
renal impairment < 60 ml/min, liver disease, hemoglobin < 10 g/dl), cardiovascular risk
factors (arterial hypertension, diabetes mellitus, dyslipidemia, current smoking, history of
stroke, coronaropathy, stent, peripheral arterial disease, atrial fibrillation). Variables with a P
value <0.15 were entered into the final multiple regression analysis which provided
odds ratio (OR) and corresponding 95% confidence interval (95% CI). In multivariate
analysis, variables were selected on the following basis: 1) p-value <0.15 in univariate
analysis, 2) prevalence >3%, 3) clinical relevance and 4) less than 2% of missing data. Prior to
the multivariate analysis, correlations and interactions were systematically searched
between variables of interest. Factors with a p value < 0.05 in the multivariate analysis were
considered as independent confounding factors. The association between the decision to
stop antiplatelet therapy and the risk of event (clinically relevant bleeding and
cardiovascular events) was then determined using a logistic regression model adjusted on
the confounding factors. The decision to stop antiplatelet therapy was considered to be an
independent factor associated with the outcome if it had a p-value less than 0.05 in the
model.

All reported p-values are 2-sided, and a p-value of less than 0.05 was considered to be
statistically significant. Statistical analyses were performed using the SAS-Windows®
software version 9.4 (SAS Institute Inc).

RESULTS

Among the 1694 patients admitted to hospital with acute VTE and treated by
anticoagulation during the study period, 264 (15.6%) were receiving antiplatelet treatment
at the time of acute VTE diagnosis (Figure 1). Ten patients were excluded because they did
not have the follow-up visit. Finally 254 patients were included and analyzed. For 193 of

7
them, the decision to discontinue the antiplatelet therapy was retained, while the decision
to associate anticoagulant and antiplatelet therapy was retained for the 61 remaining
patients.

Figure 1: Flow Chart

Clinical characteristics of the 254 included patients are presented in Table 1. Sex ratio was
balanced, and 52% of patients were 80 years-old or older. Aspirin was the most frequent
antiplatelet used. The three most frequent bleeding risk factors were renal impairment
(14.6%), anemia (11.6%) and thrombocytopenia (9.3%). Regarding cardiovascular risk
factors, two thirds of the patients were receiving antiplatelet for secondary cardiovascular
prevention: coronaropathy (29.9%), stroke (20.9%), peripheral arterial disease (18.9%).

TABLE 1 patient clinical characteristic

Patients, n 254
Male gender 128 (50.4%)
Age (mean year ± SD) 77.0 ± 12.1
Age ≥ 80 years-old 133 (52.4%)
Body weight (mean kg ± SD) 75.3 ± 20.0
Body weight < 50 kg 17 (6.7%)
Antiplatelet at baseline
Aspirin 193 (76.3%)
Anti P2Y12 69 (27.3%)

8
Double 10 (3.9%)
Venous thrombosis history
DVT only 30 (12.3%)
SVT only 10 (4.0%)
PE 38 (15.1%)
Provoked 30 (12.9%)
Cava filter 2 (0.8%)
Bleeding risk factor
Major bleeding < 2 months 8 (3.1%)
Creatinin (mean μmol/L ± SD) 97.8 ± 47.9
Renal impairment (<15 ml/min ?) 12 (4.7%)
Renal impairment (<60 ml/min ?) 37 (14.6%)
Ethylism 14 (5.5%)
Liver disease 6 (2.4%)
Hemoglobin < 10 g/dL 29 (11.6%)
Thrombopenia < 150 G/L 23 (9.3%)
Polymedication (≥ 4 drugs) 207 (82.8%)
Cardio Vascular Risk Factor
Arterial hypertension 179 (70.5%)
Diabetes mellitus 67 (26.4%)
Dyslipidemia 106 (44.7%)
Smokers 70 (28.9%)
Active smokers 26 (10.7%)
Cardio vascular event 160 (63.0%)
History of stroke 53 (20.9%)
Coronaropathy 76 (29.9%)
Stable coronaropathy 67 (26.6%)
Stent 36 (14.3%)
Drug eluting stent 15 (6.1%)
Implantation < 12 months 31 (12.3%)
Peripheral arterial disease 48 (18.9%)
Stent 15 (5.9%)
By-pass / amputation 19 (7.5%)
Carotid atheromatosis 26 (10.2%)
Atrial fibrillation 40 (15.7%)
DVT: deep-vein thrombosis; PE: pulmonary embolism; SD: standard deviation; SVT: superficial vein thrombosis

PE was the most frequent clinical presentation of VTE (74.0%), and VTE was provoked by a
transient risk factor in 27.2% (table 2). Regarding the management of acute VTE, most of the
patients (130, 51.2%) were treated with VKA, followed by low-molecular-weight-heparin
alone (mainly because of active cancer, 68, 26.8%), and DOACs (54, 21.3%). Main
characteristics of patients according to their management are presented in the
supplementary. Among the 61 patients in whom the decision to maintain antiplatelet

9
therapy was taken, antiplatelet was aspirin in 39 (59%) patients. The proportion of combined
antiplatelet-anticoagulant therapy was stable throughout the 10 years of inclusion.

TABLE 2 - Clinical characteristics and treatment strategies for VTE

Patients, n 254

Venous thrombosis characteristics

PE ± DVT 188 (74.0%)
Proximal PE 66 (28.4%)
Intermediate PESI 75 (32.5%)
DVT without symptomatic PE 66 (26.0%)
Isolated proximal DVT 45 (17.7%)
Bilateral DVT 35 (13.8%)
Provoked 108 (42.7%)
Surgery 20 (7.9%)
Non surgical transient risk factor
Immobilization 58 (22.8%)
Oestrogen use 2 (0.8%)
Associated with cancer 42 (16.7%)
Thrombophilia 4 (1.6%)
Treatment
Thrombolysis 2 (0.8%)
Cava filter (because of perceived high bleeding risk) 3 (1.2%)
DOACs 54 (21.3%)
VKA 130 (51.2%)
Heparin / LMWH alone 68 (26.8%)
Antiplatelets associated with AC
Decision to continue antiplatelet therapy 61 (24.0%)
Aspirin alone 36 (59.0%)
Anti P2Y12 alone 24 (39.3%)
Association 1 (1.6%)
AC: anticoagulation; DOACs: direct oral anticoagulant; DVT: deep-vein thrombosis; LMWH: low-molecular
weight heparin; PE: pulmonary embolism; PESI: Pulmonary Embolism Severity Index; SD: standard deviation;
VKA: vitamin-K antagonist

The confounding factors associated with the decision to stop the antiplatelet therapy were
age ≥80 years-old (OR 2.65 (95%CI 1.31 ; 5.36)) and the use of DOACs for VTE therapy (OR
2.96 (95% CI 1.07 ; 8.22)), while the confounding factors associated with the decision to
associate an antiplatelet therapy to the anticoagulant therapy were having an association of
10
antiplatelet at baseline (OR 0.07 (95% CI 0.01 ; 0.38)), a history of coronaropathy (OR 0.21
(95% CI 0.10 ; 0.43)) or a history of peripheral arterial disease (OR 0.29 (95%CI 0.13 ; 0.64))
(table 3).

TABLE 3 - Factors associated with the decision to stop or to continue antiplatelet treatment

OR multivariate (95% CI) p-value

Factors associated with the decision to STOP antiplatelet therapy (n=193)

Age ≥ 80 years-old 2.65 (1.31;5.36) 0.007

Renal impairment (<60 ml/min) 2.18 (0.65 ; 7.31) NS

Type of AC: DOACS 2.96 (1.07 ; 8.22) 0.04

Factors associated with the decision to CONTINUE antiplatelet therapy (n=61)

Type of antiplatelet at baseline
AntiP2Y12 alone 0.67 (0.31 ; 1.45) 0.008
Association 0.07 (0.01 ; 0.38)
Major bleeding < 2 months 0.30 (0.05 ; 1.65) NS
Liver disease 0.43 (0.06 ; 2.89) NS
Coronaropathy 0.21 (0.10;0.43) < 0.0001
Stent 0.39 (0.13 ; 1.16) NS
Peripheral arterial disease 0.29 (0.13; 0.64) 0.002
AC: anticoagulation; DOACs: direct oral anticoagulant; NS: not significant; OR (95% CI): odds
ratio (95% confidence interval)

During the mean follow-up of 18.7 ± 20.6 months (median: 11.3 months), 25 patients (9.8%)
experienced a clinically relevant bleeding and 17 patients (6.7%) a cardiovascular event
(table 4). Recurrent VTE occurred in 3 patients (1.2%) and 38 patients (15.0%) died during
the follow-up.

11
TABLE 4 - Clinical outcomes during follow-up

Patients, n 254

Mean follow up (months ± SD) 18.7 ± 20.6

Median follow up (months) 11.3
Bleeding 26 (10.2%)
Clinically Relevant Bleeding 25 (9.8%)
Time (mean months ± SD) 7.3 ± 13.2
Major bleeding 10 (3.9%)
Intracranial bleeding 3 (1.2%)
Gastro intestinal bleeding 3 (1.2%)
Clinically relevant non major bleeding 15 (5.9%)
Gastro intestinal bleeding 6 (2.4%)
Recurrent VTE / Extension 3 (1.2%)
Time (mean months ± SD) 5.9 ± 6.5
Cardiovascular Event 17 (6.7%)
Time (mean months ± SD) 11.3 ± 11.8
Ischemic stroke 5 (2.0%)
Cardiac event 5 (2.0%)
Drug eluting stent 3 (1.2%)
Limb ischemia 7 (2.8%)
Death 38 (15.0%)
Time (mean months ± SD) 8.2 ± 8.4
Fatal PE 1 (0.4%)
Fatal bleeding 4 (1.6%)
Fatal ischemic cardiovascular event 2 (0.8%)
Fatal neoplasia 13 (5.3%)
Other cause of deaths 12 (4.9%)
Unknown cause of deaths 6 (2.4%)
SD: standard deviation

Adjusted on the previous confounding factors (table 3), the interruption of antiplatelet
therapy was associated with a non-significant 46% decrease in the risk of clinically relevant
bleeding (OR 0.54 (95% CI 0.16; 1.78)), and a non-significant 68% increase in the risk of
cardiovascular events (OR 1.68 (95% CI 0.44; 6.46)) (Table 5).

Table 5: Association between the decision to stop antiplatelet treatment and the risk of
clinically relevant bleeding or cardiovascular events

Association between the interruption of OR (95% CI) p-value

antiplatelet treatment and the risk of:

12
Clinically relevant bleeding 0.54 (0.16 ; 1.78) 0.31

Cardiovascular events 1.68 (0.44 ; 6.46) 0.45

13
DISCUSSION

Among patients admitted to hospital for an acute VTE, we found that 15.6% were
receiving antiplatelet therapy at the time of VTE diagnosis, and that the decision to maintain
the antiplatelet therapy on top of the anticoagulant therapy was retained in more than one
in four patients. Age≥80 years and use of DOACs for VTE therapy were associated with the
decision to stop the antiplatelet therapy, while having an association of antiplatelet at
baseline, a history of coronaropathy or of peripheral arterial disease were associated with
the decision to associate an antiplatelet therapy to the anticoagulant therapy. After
adjustment, the decision to stop antiplatelet therapy was associated with a non-significant
decrease in the risk of bleeding and a non-significant increase in the risk of cardiovascular
events.

The high proportion of patients under antiplatelet therapy at diagnosis of acute VTE
is explained by the association between VTE and cardiovascular diseases, age being a major
risk factor for both [12-13]. A similar proportion was noted in the AMPLIFY trial [14], in
which 15% of the 5365 patients were receiving concomitant antiplatelet therapy at inclusion.
Besides confirming the frequency of this practice, our study provides interesting data
concerning the phenotype of the patients involved. In contrast to the population included in
the AMPLIFY study, our study population comprised consecutive patients admitted to clinical
wards of two public hospitals, who were older, less frequently male, and more often
presented renal impairment, cancer, cardiovascular risk factors and/or a history of
cardiovascular events. Such differences in baseline characteristics may hamper the
extrapolation of data derived from subgroup analyses conducted in phase 3 trials to clinical
practice. Dedicated studies in patients with an increased risk of both cardiovascular events
and bleeding, such as those included in our analyses, are needed.

Clinician decided to stop antiplatelet therapy in around 75% of our patients following
acute VTE diagnosis. As our teams had substantial experience in the field of antithrombotic
treatment, and were consequently aware of the increased risk of bleeding in patients
receiving concomitant anticoagulant and antiplatelet therapy, we were surprised to find that
almost a quarter of patients were discharged with this combined treatment. This proportion

14
of patients is lower than that reported by Tzoran et al. (about 40%) [4], and much lower than
expected from an French survey[15, 16] but is still significant. It may be explained by the
clinical characteristics of our patients, who more frequently had a history of cardiovascular
events with an increased risk of ischemic complications. Recently, Golemi et al. [14] found
that patients with acute VTE may suffer from major acute cardiovascular events (MACE) and
major adverse limb events (MALE) despite receiving anticoagulant therapy during follow-up,
the presence of cancer being a major independent risk factor. This point is important to
stress, as cancer was more frequent in the patients discharged with concomitant antiplatelet
and anticoagulant therapy in our study. This finding points to the need for better
antithrombotic options in patients with VTE and at increased risk of cardiovascular events.

It is not surprising that being older was a factor associated with the decision to stop
antiplatelet agent, as older patients have an increased risk of bleeding. However, use of
DOACs for VTE therapy was also associated with the decision to stop the antiplatelet
therapy. This may reflect the modification of our prescription with time, despite the
proportion of patients discharged with antiplatelet and anticoagulant remain stable
throughout the 10 years of inclusion. Factors associated with the decision to continue
antiplatelet agent seems logical, having cardio-vascular disease such as coronaropathy or
peripheral arterial disease or having an association of antiplatelet, what let think that the
cardiovascular disease was more severe.

Our results suggest that the decision of stopping the antiplatelet was associated with
a trend toward a decreased risk of CRB but an increased risk of cardiovascular events. These
results, obtained in unselected patients with acute VTE treated in two public tertiary
hospitals, are rather similar to those found in prevalent patients anticoagulated for VTE. Of
note, the rate of major bleeding in our study (3.9% after a median follow-up of 7.3 months)
was quite similar to that found by Schaefer et al. [5] in their recently reported retrospective
multicenter cohort study of prevalent patients prescribed VKA and aspirin without a clear
indication (5.7% at 12 months). The longer follow-up in our study may explain the difference
between our results and those obtained by Tzoran et al. in patients with acute VTE [4].

Of note, the two subgroups couldn’t be compared, because of an obvious confusion

bias. Only a randomized controlled trial would be able to compare the two strategies, in

15
order to determine the best antithrombotic therapy, in patients with VTE diagnosed under
antiplatelet drugs. This will be the primary aim of the BAT-VTE trial, coordinated by the
INNOVTE network (https://www.innovte-thrombosisnetwork.eu/en/innovte-network-0). In
the same manner, results could not be presented in terms of patients-years, as the risks of
events are nor similar, nor constant, all along the time (as illustrated by the timing of
bleeding, recurrent VTE and cardiovascular events).

Before being in a position to propose a safer but sufficiently effective strategy, what
can we do? Extrapolating from ESC guidelines, it seems that if the clinician considers
concomitant antiplatelet and anticoagulant therapy to be mandatory, the use of a direct oral
anticoagulant may be a better option than a VKA [17]. Indeed, in the AUGUSTUS trial [17],
patients with AF associated with an acute coronary syndrome and/or percutaneous coronary
interventions had a lower bleeding risk and were less likely to be hospitalized if they were
treated with apixaban (5 mg twice daily or 2.5 mg twice daily if they met two or more of the
dose-reduction criteria) plus a P2Y12 inhibitor vs a VKA plus a P2Y12 inhibitor. The PIONEER
AF-PCI trial [18] also showed a higher risk of bleeding in patients with AF following a
percutaneous coronary intervention involving stent placement who were treated with
warfarin vs rivaroxaban (15 mg once daily or 2.5 mg twice daily). In the AMPLIFY trial,
concomitant anticoagulant and anti-platelet therapy resulted in a proportionally similar
increase in major bleeding in patients randomized to apixaban or conventional therapy, but
there were fewer major bleeds with apixaban [14]. The risk of gastrointestinal bleeding
varies with the type of antiplatelet drug (aspirin vs P2Y12 inhibitor). In our study, the
proportion of patients prescribed a P2Y12 inhibitor seemed to increase following the
initiation of anticoagulant therapy, although still remaining below the proportion prescribed
aspirin. This suggests that clinicians may prefer to avoid the use of aspirin in combination
with anticoagulant therapy. However, the optimal choice of antiplatelet therapy when
combined with an anticoagulant drug needs further research.

Our study suffers from the limitations inherent in its design. We performed a post-
hoc analysis of prospective registries of consecutive patients admitted to hospital for acute

16
VTE. The decision to maintain or discontinue ongoing antiplatelet therapy was left to each
clinician, even though we all work within the same team, with weekly discussions of
antithrombotic strategies. Moreover, retrospective analysis may involve the risk of missing
data. However, most of the patients admitted to our hospitals for acute VTE are seen later
on in our outpatient clinic for follow-up. The demographic size of our metropolitan areas
reduces the risk of missing information. Finally, we cannot rule out the possibility that some
patients might have changed (or not taken) their treatment during the follow-up. That is why
the groups were constructed according to discharge treatment. Finally, our study may lack
statistical power (for example to conclude on the risk of major bleeding), although all the
odds ratios were increased to the same extent proportionally.

The conclusion of our study is that among the patients under antiplatelet therapy
when diagnosed with acute VTE, clinicians discharged a quarter of them with concomitant
anticoagulant and antiplatelet therapy. Our results suggest that the choice of these
concomitant therapies may be associated with a trend toward better cardiovascular
prevention, but with a possible increased risk of clinically relevant bleeding during the
follow-up. Further dedicated research is needed to assess which patients should be
discharged with concomitant anticoagulant and antiplatelet therapy, and to optimize this
combination therapy, in the era of direct oral anticoagulants.

17
AUTHOR DECLARATIONS

- Ethics approval and consent to participate : The study was approved by the local
ethical committee (Terre d’éthique, N° IRBN402018/CHUSTE)

- Consent for publication : 'Not applicable'

- Availability of data and materials : All patients provided their consent to participate in
the study according to local regulations. Data were recorded on a computer-based
case report form (declared to the French “Commission Nationale de l’Informatique et
des Libertés” [CNIL]).

- Competing interests : None

- Funding: No funding was obtained for this work.

- Authors' contributions : Marie Giraud, Isabelle Mahé and Laurent Bertoletti designed
the study. Marie Giraud, Lucile Cognet and Hélène Helfer collected the data. Céline
Chapelle and Silvy Laporte did the statistical analysis. All authors analyzed,
interpreted the data, and drafted the manuscript. All authors made substantial
contributions to the conception and design of the study, revised the manuscript, and
approved the final version for publication.

- Acknowledgements: The authors warmly thank Ms Paula Harry for revising the
English.

- Authors' information (optional): Part of the results has been presented during the
2020 ISTH.

COMPLIANCE WITH ETHICAL STANDARDS

- Ethics approval and consent to participate: All patients provided their consent to
participate in the study according to local regulations. Data were recorded on a
computer-based case report form (declared to the French “Commission Nationale de
l’Informatique et des Libertés” [CNIL]). The study was approved by the local ethical
committee (Terre d’éthique, N° IRBN402018/CHUSTE)

- Disclosure of potential conflicts of interest : Dr. MAHE reports grants, personal fees
and non-financial support from BMSPfizer, personal fees and non-financial support
from Bayer, grants, personal fees and non-financial support from Leo-Pharma,
outside the submitted work; Dr. BERTOLETTI reports grants and personal fees from

18
 SANOFI, grants, personal fees and non-financial support from LEO-PHARMA, personal
fees and non-financial support from ASPEN, during the conduct of the study; Dr.
Laporte reports grants from LeoPharma, grants and personal fees from Bayer
HealthCare, personal fees from Pfizer, outside the submitted work; Dr. MISMETTI
reports personal fees from Bayer HealthCare, personal fees from Pfizer, personal fees
from Boehringer Ingelheim outside the submitted work; Mrs. CHAPELLE has nothing
to disclose; Dr. ACASSAT reports non financial support from LeoPharma, Astra zeneca
and Pfizer outside the submitted work, Dr. HELFER has nothing to disclose, Dr.
COGNET has nothing to disclose. Dr CATELLA has nothing to disclose. Dr GIRAUD has
nothing to disclose

- Research involving Human Participants and/or Animals : 'Not applicable'

- Informed consent : 'Not applicable'

19
REFERENCES

1. Seiler E, Limacher A, Méan M, et al (2017) Derivation and validation of a novel bleeding risk
score for elderly patients with venous thromboembolism on extended anticoagulation. 1930–
1936

2. Davidson BL, Verheijen S, Lensing AWA, et al (2014) Bleeding risk of patients with acute
venous thromboembolism taking nonsteroidal anti-inflammatory drugs or aspirin. JAMA
Intern Med. https://doi.org/10.1001/jamainternmed.2014.946

3. Cohen AT, Agnelli G, Buller HR, et al (2019) Characteristics and Outcomes in Patients with
Venous Thromboembolism Taking Concomitant Anti-Platelet Agents and Anticoagulants in the
AMPLIFY Trial. Thromb Haemost 119:461–466. https://doi.org/10.1055/s-0038-1676983

4. Davidson BL, Verheijen S, Lensing AWA, et al (2014) Bleeding risk of patients with acute
venous thromboembolism taking nonsteroidal anti-inflammatory drugs or aspirin. JAMA
Intern Med 174:947–53. https://doi.org/10.1001/jamainternmed.2014.946

5. Tzoran I, Brenner B, Sakharov G, et al (2014) Clinical outcome in patients with venous

thromboembolism receiving concomitant anticoagulant and antiplatelet therapy. Eur J Intern
Med 25:821–5. https://doi.org/10.1016/j.ejim.2014.09.010

6. Schaefer JK, Li Y, Gu X, et al (2019) Association of Adding Aspirin to Warfarin Therapy Without

an Apparent Indication With Bleeding and Other Adverse Events. JAMA Intern Med 179:533–
541. https://doi.org/10.1001/jamainternmed.2018.7816

7. Dentali F, Douketis JD, Lim W, Crowther M (2007) Combined aspirin-oral anticoagulant

therapy compared with oral anticoagulant therapy alone among patients at risk for
cardiovascular disease: a meta-analysis of randomized trials. Arch Intern Med 167:117–24.
https://doi.org/10.1001/archinte.167.2.117

8. Hansen ML1, Sørensen R, Clausen MT, Fog-Petersen ML, Raunsø J, Gadsbøll N, Gislason GH,
Folke F, Andersen SS, Schramm TK, Abildstrøm SZ, Poulsen HE, Køber L T-PC (2010) Risk of
Bleeding With Single, Dual, or Triple Therapy With Warfarin, Aspirin, and Clopidogrel in
Patients With Atrial Fibrillation. Arch Intern Med 170:1433–1441

9. Kirchhof P, Uk C, Uk DK, et al (2016) 2016 ESC Guidelines for the management of atrial
fibrillation developed in collaboration with EACTS The Task Force for the management of
atrial fibrillation of the European Society of Cardiology ( ESC ) Developed with the special
contribution of the Europ. 2893–2962. https://doi.org/10.1093/eurheartj/ehw210

10. Tzoran I, Brenner B, Sakharov G, et al (2014) Clinical outcome in patients with venous
thromboembolism receiving concomitant anticoagulant and antiplatelet therapy. Eur J Intern
Med. https://doi.org/10.1016/j.ejim.2014.09.010

11. EINSTEIN Investigators, Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus
AS, Lensing AW, Misselwitz F, Prins MH, Raskob GE, Segers A, Verhamme P, Wells P, Agnelli G,
Bounameaux H, Cohen A, Davidson BL, Piovella F SS (2010) Supplementary Appendix, The
EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J
Med. https://doi.org/10.1056/NEJMoa1207541

12. S. SCHULMAN* and C. KEARON (2005) Definition of major bleeding in clinical investigations of
antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 692–694

13. Bahit MC, Lopes RD, Wojdyla DM, et al (2017) Non-major bleeding with apixaban versus

20
 warfarin in patients with atrial fi brillation. 623–628. https://doi.org/10.1136/heartjnl-2016-
309901

14. Cohen AT, Agnelli G, Buller HR, et al (2019) Characteristics and Outcomes in Patients with
Venous Thromboembolism Taking Concomitant Anti-Platelet Agents and Anticoagulants in the
AMPLIFY Trial

15. Fayol A, Lanéelle D, Hoffmann C, et al (2019) French vascular physicians’ practices in

indicating antiplatelet and anticoagulation therapy in venous thromboembolism. Vasa
48:355–360. https://doi.org/10.1024/0301-1526/a000789

16. Fayol A, Plaisance L, Poenou G, et al (2020) Management of the antiplatelet therapy during
the diagnosis of venous thromboembolism disease: A national survey of French general
practitioners’ compared to the French vascular physicians’ management. J Med Vasc 45:107–
113. https://doi.org/10.1016/j.jdmv.2020.04.002

17. Agnelli G, Buller HR, Cohen A, et al (2013) Apixaban for Extended Treatment of Venous
Thromboembolism. N Engl J Med. https://doi.org/10.1056/NEJMoa1207541

18. Gibson CM1, Mehran R2, Bode C3, Halperin J2, Verheugt F4, Wildgoose P5, van Eickels M6, Lip
GY7, Cohen M8, Husted S9, Peterson E10 FK An open-label, randomized, controlled,
multicenter study exploring two treatment strategies of rivaroxaban and a dose-adjusted oral
vitamin K antagonist treatment strategy in subjects with atrial fibrillation who undergo
percutaneous coronary intervention. Am Hear J. https://doi.org/10.1016/j.ahj.2014.12.006

21