Long-term outcome after heparin plus edoxaban versus heparin plus vitamin K antagonists for acute deep vein thrombosis and pulmonary embolism

Post thrombotic syndrome (PTS) and chronic thromboembolic pulmonary
hypertension (CTEPH) are long-term complications of deep vein thrombosis (DVT)
and pulmonary embolism (PE), respectively. For development of PTS, it is known
that poor quality treatment with vitamin K antagonists (VKA) is a risk factor.
Direct oral anticoagulants (DOACs) have a more stable pharmacologic profile
than VKA. We hypothesize that treatment of venous thromboembolism (VTE) with
the direct oral anticoagulant (DOAC) edoxaban leads to improved thrombus
resolution and thereby less long-term sequelae, translating into better quality
of life and a lower incidence of both PTS and CTEPH, compared to treatment with
heparin followed by VKA.

To assess the long-term PE-related Quality of Life and to assess the cumulative
incidence of PTS in patients with acute DVT, treated with heparin plus edoxaban
in comparison to patients treated with heparin plus warfarin. Furthermore, the
feasibility of pro-active case-finding of CTEPH will be evaluated in selected
patients with acute PE by use of a recently derived risk stratification score,
based on clinical variables and detailed assessment of index computed
tomography pulmonary angiography (CTPA) scans.

This investigator-initiated cohort study includes patients who participated in
the Hokusai venous thromboembolism (VTE) trial. The Hokusai VTE trial was a
randomized, double-blind, non-inferiority trial that compared the efficacy and
safety of heparin (enoxaparin or unfractionated heparin) followed by edoxaban
with heparin (enoxaparin or unfractionated heparin) followed by warfarin
(target INR 2-3) in patients with acute, symptomatic VTE. A subset of centers
that participated in the Hokusai VTE trial will be invited to collect follow-of
previously enrolled patients at least 2 years after the index VTE. Patients
with an index DVT will be asked to complete the VEINES-QOL questionnaire, and
to assess the venous disease-specific quality of life the Villalta score will
be calculated. The objectively and subjectively obtained Villalta score will be
compared. Among patients with an index PE, the QoL will be assessed by the
validated generic (SF-36) and pulmonary embolism specific (PEmbQoL)
questionnaires. Patients diagnosed with both PE and DVT at index will be
examined for PTS and will be asked the complete all questionnaires. In
addition, the CTEPH risk stratification score will be assessed in a substudy
among 1000 HOKUSAI-PE patients of which detailed CTPA scans are already
available, and selective follow-up of high-risk patients will be performed with
echocardiography in centers that are willing to participate in the substudy
(target n= 250).

Patients of selected centres will be requested to enrol in this study. Patients
will be invited by the participating centres. For Hokusai DVT patients, the
single hospital visit will included an examination of the affected leg and
patients are asked to fill out 2 questionnaires. Hokusai PE patients will be
asked to only complete the questionnaires. When patients are identified as a
high risk patient for CTEPH according to the CTEPH risk stratification score,
additional follow-up will be performed with echocardiography and standard care
for CTEPH might follow.

All VTE patients will be asked to visit the hospital on one occasion for
physical examination and to complete one, two or three QoL questionnaires. For
PE patients that are classified as having a high risk of developing CTEPH,
additional echocardiography will be performed. No serious risks are associated
with echocardiography, but false positive or incidental findings can be
regarded as a burden to patients. The study has some potential benefits. When
CTEPH is diagnosed, before end stage right ventricular dysfunction has
occurred, it may be curable by a surgical intervention.