Discussion
The main findings of this study are that therapeutic anticoagulation
used prior to SARS-CoV-2 infection lowers the risk of pulmonary embolism
but does not have an effect on other COVID-19 related outcomes in
hospitalized COVID-19 patients, including in-hospital mortality. In
addition, we did not observe differences in outcomes between DOAC or
VKA-treated subgroups.
The acute inflammatory phenomenon in COVID-19 amplifies
hypercoagulability and increases the risk of thrombosis even under
prophylaxis of LMWH.21 It has been hypothesized that
therapeutic anticoagulation used prior to infection could improve the
prognosis of COVID-19 by hampering coagulation activation. Indeed,
previous studies showed that the use of therapeutic anticoagulation at
hospital admission resulted in a lower incidence of VTE compared to
thromboprophylaxis alone.23,24 Other studies, however,
showed ambivalent results on COVID-19 severity and mortality due to
comparison of dissimilar cohorts and lack of proper statistical
adjustments for imbalances in baseline characteristics including
comorbidities.26,27,31 Tremblay et al. also used a
propensity score-matched comparison and found no statistically
significant difference in mortality, time to mechanical ventilation, or
hospitalization when comparing patients with and without therapeutic
oral anticoagulation prior to SARS-CoV-2 infection.27However, they included both ambulatory and hospitalized patients, and
only adjusted for age, sex, race, Charlson Comorbidity Index and obesity
in their propensity-score analysis while we illustrated that adjustment
for more potential confounders is relevant. Moreover, they did not
include thrombotic complications as an outcome parameter whereas our
study showed a benefit on PE incidence, but not on other clinical
endpoints.
This is also the first study that investigated the effects of
therapeutic anticoagulation subgroups, i.e. vitamin K antagonists (VKAs)
and direct oral anticoagulants (DOACs), in hospitalized COVID-19
patients. There are different hypotheses why VKAs could have unfavorable
effects, and DOACs on the other hand could be of benefit in COVID-19.
Dofferhoff et al detected reduced extrahepatic vitamin K status in
patients with COVID-19 and showed that low vitamin K status was related
to poor prognosis in these patients.28 VKA’s are
evident causes of reduced vitamin K status, but the relationship between
VKA versus other therapeutic anticoagulation on the prognosis of
COVID-19 patients has never been studied before.
Our study has several limitations that need to be addressed. Most
importantly, its observational and retrospective nature limit causal
inference, although the propensity score matching increases the
credibility of our observations. Noteworthy, propensity score matching
is often criticized because of its dependence on the included
covariates. Confounders not included in the propensity score could lead
to significant bias. However, in our study the prior visualization of
relevant covariates in the DAG and the subsequent high and relevant
number of included covariates in the propensity score matching, make
this a valid approach. Other limitations are that there was no routine
screening for pulmonary embolism, which may have resulted in
underdiagnosis of this outcome especially in patients already treated
with therapeutic anticoagulation.
Strengths of our study include the rigorous statistical analysis with
thorough adjustment for confounding to properly investigate the
treatment effect of prior therapeutic anticoagulation on different
clinically relevant outcomes in a large cohort of hospitalized COVID-19
patients. Furthermore, we are the first to investigate the effect of
therapeutic anticoagulation subgroups, i.e. vitamin K antagonists and
DOACs.
In summary, although prior therapeutic anticoagulation use is associated
with reduced PE occurrence, it is not associated with better outcome
parameters in hospitalized COVID-19 patients in terms of all-cause
mortality, ICU admittance, need for mechanical ventilation, and length
of hospital stay. Secondary analysis between subgroups also showed no
differences in clinical outcomes between VKA or DOAC treated patients.